Aminopyridine derivatives as phosphatidylinositol phosphate kinase inhibitors

ABSTRACT

The invention relates to inhibitors of PI5P4K inhibitors useful in the treatment of cancers, neurodegenerative diseases, inflammatory disorders, and metabolic diseases, having the Formula:where A, B, R1, X1, X2, and W are described herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase Application, filed under 35U.S.C. 371, of International Application No. PCT/US2018/067264, filed onDec. 21, 2018, which claims the benefit of priority of U.S. ProvisionalApplication No. 62/609,568, filed Dec. 22, 2017, which the entiredisclosure of each are incorporated herein by reference in theirentirety.

FIELD OF INVENTION

The present invention is directed to inhibitors ofphosphatidylinositol-5-phosphate-4-kinase (PI5P4K) useful in thetreatment of diseases or disorders associated with PI5P4K enzymes. Inparticular, the invention is concerned with compounds and compositionsinhibiting PI5P4K, methods of treating diseases or disorders associatedwith PI5P4K, and methods of synthesis of these compounds.

BACKGROUND OF THE INVENTION

A minor but ubiquitous component of cells, phosphoinositol lipids arepivotal players in many intracellular signal transduction pathways.Phosphoinositol lipids are formed when phosphatidylinositol (PtdIns) isconverted, by the catalytic action of lipid kinases, topolyphosphoinositides. As a prototypic example, the membrane associatedphospholipid, phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2), isformed by two successive phosphorylations of PtdIns by thephosphatidylinositol phosphate kinases (PIP kinases).

PtdIns(4,5)P2 is a substrate for phospholipase C (PLC) and is convertedinto the second messengers inositol-1,4,5-trisphosphate anddiacylglycerol (DAG). Phosphoinositides are involved in regulating abroad spectrum of activities from cytoskeletal assembly and motility tovesicle trafficking and exocytosis to transduction of intracellularsignals including stimulating the release of intracellular calciumstores (Hinchliffe et al., Biochem. Soc. Trans., 1999, 27, 657-661).

PIP kinases comprise a unique and promiscuous family of enzymes thatcatalyze the production of poly-phosphorylated inositol lipids frommono-phosphorylated phosphoinositides. isolation and purification ofseveral different PIP kinase enzymes able to catalyze phosphorylation ofphosphatidylinositol 4-phosphate and produce PtdIns(4,5)P2 led to thefurther categorization of these enzymes, dubbed the phosphatidylinositol4-phosphate 5-kinases (PIP5Ks), into two types having differentactivities. The PIP kinases have no homology to other lipid or proteinkinases at the primary sequence level, and are distinguished from eachother by their lack of immuno-cross reactivity and by the fact that typeI PIP5Ks are stimulated in vitro by phosphatidic acid, whereas the typeII PIP5Ks are not. Furthermore, the recent discovery that the type IIPTP5Ks are able to phosphorylate multiple lipid substrates in vitrosuggests that this family of kinases is potentially able to generateseveral distinct, often subcellularly compartmentalized, phosphoinositolproducts for regulation of a variety of physiologically importantprocesses (Hinchliffe et al., Biochem. Soc. Trans., 1999, 27, 657-661).

One particular species of PI, phosphatidylinositol 5-phosphate (PI5P),has been implicated in the regulation of the tumor suppressor ING2 andthe oncogene AKT. The phosphatidylinositol 5-phosphate 4-kinase (PI5P4K)family (α, β, γ isoforms) catalyzes the conversion of PI5P to PI4, 5 P2.These enzymes therefore represent one means by which cells can regulateendogenous PI5P levels. Mice deficient for PI5P4Kβ (PI5P4Kβ−/−) havebeen shown to exhibit enhanced insulin sensitivity and activation of AKTin skeletal muscle.

The pharmacological modulation of PIP5KII-beta activity and/orexpression is therefore believed to be an appropriate point oftherapeutic intervention in pathological conditions in which celldifferentiation, proliferation, and/or motility are compromised, such ascancer or inflammation, and in metabolic disorders.

Currently, there are no known therapeutic agents which effectivelyinhibit the synthesis of PIP5KII-beta. Inhibition of PI5P4K with smallmolecule inhibitors, therefore, has the potential to be a treatment forcancers and other disorders. For this reason, there remains aconsiderable need for novel and potent small molecule inhibitors andagents capable of effectively inhibiting PIP5KII-beta function.

SUMMARY OF THE INVENTION

A first aspect of the invention relates to compounds of Formula (I):

and pharmaceutically acceptable salts, prodrugs, solvates, hydrates,isomers, and tautomers thereof,wherein:

-   -   A is C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₂₋₆ alkynyl, aryl,        spiroheterocyclyl, heterocyclyl, or 6-membered heteroaryl,        wherein the cycloalkyl, heterocyclyl, aryl spiroheterocyclyl, or        heteroaryl is optionally substituted with one or more R₅;    -   B is heterocyclyl or heteroaryl, wherein the heterocyclyl group        is optionally substituted with one or more R₇ and the heteroaryl        is optionally substituted with one or more R₈, provided that        when B is heteroaryl, B is not bonded through its heteroatom;    -   X₁ is C(R₅);    -   X₂ is C(R₅) or N;    -   W is C(R₆) or N; provided that only one of X₁, X₂, or W can be        N;    -   R₁ is —N(R₂)C(O)R₃, —C(O)N(R₂)(R₃), —S(O)₂N(R₂)(R₃),        —N(R₂)S(O)₂R₃, —R₂C(O)N(R₂)(R₃), or heteroaryl, wherein        heteroaryl is optionally substituted with one or more R₇;    -   R₂ is independently, at each occurrence, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynyl        is optionally substituted with one or more R₄;    -   R₃ is independently, at each occurrence, —H, C₁₋₆ alkyl, C₂₋₆        alkenyl, or C₂₋₆ alkynyl, wherein the alkyl, alkenyl, or alkynyl        is optionally substituted with one or more R₄; or    -   R₂ and R₃ when taken together with the atom to which they are        each attached form a heterocycle optionally substituted with one        or more R₄;    -   R₄ is independently —H, halogen, —OH, —NH₂, —NO₂, —CN, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or        heteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,        aryl, or heteroaryl is optionally substituted with one or more        R₇;    -   R₅ is independently —H, halogen, —OH, —CN, C₁₋₆ alkyl, methoxy,        —OC₃-C₆ alkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or        heteroaryl;    -   R₆ is —H, halogen, —OH, —NH₂, —NO₂, —CN, —CO₂H, —C(O)NH₂, C₁₋₆        alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, —O—C₃₋₈ cycloalkyl, or        C₁₋₆ alkyl, wherein the alkyl, alkoxy, heterocyclyl, or        cycloalkyl is optionally substituted with —OH, C₁₋₆ alkyl, C₁₋₆        alkoxy, C₃₋₈ cycloalkyl, —NH₂, —NH(C₁₋₆ alkyl), or —N(C₁₋₆        alkyl)₂; or    -   R₅ and R₆ when on adjacent carbons and when taken together with        the carbon atom to which they are each attached form a 5- to        6-membered heteroaryl ring;    -   R₇ is —H, halogen, —OH, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈        cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the        alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl or heteroaryl is        optionally substituted with one or more R₁₄;    -   R₈ is —H, —CN, oxo, C₁₋₆ alkyl, heterocyclyl, aryl, heteroaryl        —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),        —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, —C(O)R₉, —N(R₉)(R₁₀), —OR₁₀,        —C(O)R₉—NR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀), wherein the        alkyl, heterocyclyl, aryl, or heteroaryl is optionally        substituted with one or more R₁₅; or    -   two R₈ groups, together with the atoms to which they are        attached, form a C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl,        spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl,        wherein the cycloalkyl, spirocycloalkyl, spiroheterocycloalkyl,        or heterocyclyl, is optionally substituted with one or more R₁₅        or the aryl or heteroaryl is optionally substituted with one or        more R₂₄;    -   each R₉ or R₁₀ is independently, at each occurrence, —H, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, aryl,        heteroaryl, or heterocyclyl, wherein the alkyl, cycloalkyl, or        heterocyclyl is optionally substituted with one or more R₁₁; or    -   R₉ and R₁₀ when taken together with the atom to which they are        each attached form a heterocycle ring optionally substituted        with one or more R₁₂;    -   R₁₁ is —H, halogen, —CN, oxo, —OH, —N(R₂₃)(R₂₅), —OR₂₃, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl,        aryl, —C(O)R₁₇, —C(O)R₁₇, —C(O)OR₁₇, —OC(O)R₁₇, or        —C(O)N(R₂₃)(R₂₃), wherein the alkyl, alkoxy, aryl, heterocyclyl,        heteroaryl, or cycloalkyl is optionally substituted with one or        more R₁₇;    -   R₁₂ is independently —C(O)OR₂₁, —C(O)R₁₃; oxo, —OH, C₁₋₆ alkyl,        heterocycle, —(C₁₋₆ alkyl)-heteroaryl, —(C₁₋₆        alkyl)-heterocycle, —(C₁₋₆alkyl)-C₃₋₆ cycloalkyl, —(C₁₋₆        alkyl)-aryl, wherein any alkyl, heteroaryl, heterocycle,        cycloalkyl, or aryl is optionally substituted with one or more        R₁₈; or    -   two R₁₂ together with the atoms to which they are attached form        an aryl ring optionally substituted with one or more R₁₈;    -   each R₁₃ is aryl, heterocyclyl, cycloalkyl, or heteroaryl,        wherein the aryl or heteroaryl group is optionally substituted        with one or more R₁₉ and the heterocyclyl or cycloalkyl is        optionally substituted with one or more R₂₀;    -   R₁₄ is independently —H, halogen, —CN, —NO₂, —OH, —NH₂, C₁₋₆        alkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl;    -   R₁₅ is —H, halogen, oxo, —OH, —NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₆        alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, heteroaryl,        —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃,        —SO₂R₂₃, —N(R₂₃)C(O)—Ar—N(R₂₃)-G or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G,        wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl,        or aryl is optionally substituted with one or more R₂₃; or    -   two R₁₅ groups, together with the atoms to which they are        attached, form a heterocyclyl, C₃₋₆ cycloalkyl, C₅₋₆        spirocycloalkyl, aryl, or heteroaryl, wherein cycloalkyl,        heterocyclyl, spirocycloalkyl, heteroaryl, or aryl is optionally        substituted with one or more R₂₀;    -   Ar is aryl;    -   G is —H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)OR₂₃,        —C(O)CH═CHCH₂N(R₂₃)(R₂₃), or —C(O)N(R₂₁)(R₂₃); or    -   two R₁₅ when on adjacent atoms may be taken together with the        atoms to which they are each attached to form a heterocycle        optionally substituted with one or more R₁₆;    -   R₁₆ is independently C₁₋₆ alkyl, C₃₋₆ cycloalkyl, —C(O)R₂₃,        —C(O)R₂₃, —C(O)OR₂₃, —S(O)₂R₂₃, or oxo;    -   R₁₇ is —H, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, heteroaryl, aryl,        —N(R₂₃)(R₂₃), —N(R₂₃)C(O)OR₂₃, —C(O)N(R₂₃)(R₂₃), —N(R₂₃)C(O)        R₂₃, —N(R₂₃)C(O)—U—Z, or —N(R₂₃)C(O)—U—N(R₂₃)—Z;    -   Z is —H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl,        C₃₋₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, or        —C(O)—U—N(R₂₃)(R₂₃);    -   U is —(CH₂)_(p)—, —(CH₂)_(p)—Ar—, —CH═CH(CH₂)_(p)—, or        heterocyclyl;    -   R₁₈ is independently C₁₋₆ alkyl, heteroaryl, heterocyclyl,        cycloalkyl, aryl, —OR₂₃, —N(R₂₃)(R₂₃), or        —N(R₂₃)C(O)—V—N(R₂₃)-E, wherein the heteroaryl, heterocyclyl,        cycloalkyl, or aryl is optionally substituted with one or more        R₁₉;    -   V is —(CH₂)_(n)—, —(CH₂)_(n)—Ar—, or —CH═CH(CH₂)_(n)—,    -   E is —H, C₁₋₆ alkyl or —C(O)—V—N(R₂₃)(R₂₃);    -   R₁₉ is halogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, —OR₂₁,        —N(R₂₁)(R₂₂), —C(O)R₂₁, —N(R₂₃)C(O)OR₂₃, —N(R₂₃)C(O)-Q-N(R₂₃)—F,        or —N(R₂₃)-Q-N(R₂₃)—F;    -   Q is —CH═CH(CH₂)_(m)—, —(CH₂)_(m)—, —(CH₂O)_(m), —(CH₂)_(m)Ar—,        or —(CH₂CH₂O)_(o)—(CH₂)_(m)—,    -   F is —H, C₁₋₆ alkyl, aryl, heteroaryl, —C(O)-Q-R₂₃, or        —C(O)-Q-N(R₂₃)(R₂₃), wherein the alkyl, aryl, or heteroaryl is        optionally substituted with one or more R₂₃; or    -   R₂₀ is independently —H, halogen, —OH, —NH₂, oxo, —C(O)R₂₁,        —OR₂₃, C₃₋₆ cycloalkyl, or C₁₋₆ alkyl; or    -   R₂₁ is —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein the        alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, heteroaryl,        or aryl is optionally substituted with one or more —H, halogen,        —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl,        heterocyclyl, heteroaryl, or aryl;    -   R₂₂ is —H, C₁₋₆ alkyl, or —C(O)R₂₃; and    -   each R₂₃ is independently —H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or        heteroaryl, wherein the alkyl, alkenyl, alkynyl, cycloalkyl,        heterocyclyl, heteroaryl, or aryl is optionally substituted with        one or more —H, halogen, —CN, —OH, —NH₂, C₁₋₆ alkyl, C₁₋₆        alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, aryl, or R₂₄;    -   R₂₄ is —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈        cycloalkyl, heterocyclyl, aryl, or heteroaryl, C(O)N(C₁₋₆        alkyl)(C₁₋₆ alkyl), —C(O)—C₁₋₆ alkyl, —C(O)—C₂₋₆ alkenyl,        —C(O)O—C₁₋₆ alkyl, wherein the alkyl, alkenyl, alkynyl,        cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally        substituted with one or more —H, halogen, —CN, —OH, —NH₂, C₁₋₆        alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl,        or aryl;    -   R₂₅ is independently C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,        wherein the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl,        heteroaryl, or aryl is optionally substituted with one or more        —H, halogen, —CN, —OH, —NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈        cycloalkyl, heterocyclyl, heteroaryl, aryl, or R₂₄;    -   each p is independently 1-4;    -   each n is independently 1-4;    -   each m is independently 1-4; and    -   each o is independently 0-4.

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of PI5P4K. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of PI5P4K an effective amount ofa compound of Formula (I), or a pharmaceutically acceptable salt,hydrate, solvate, prodrug, stereoisomer, or tautomer thereof.

Another aspect of the invention is directed to a method of inhibitingPI5P4K. The method involves administering to a patient in need thereofan effective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention relates to a method of treating aneurodegenerative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating a viralinfection or disease. The method comprises administering to a patient inneed thereof an effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of treating aninflammatory disease or condition. The method comprises administering toa patient in need thereof an effective amount of a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells and/or enhanced tumor-specificT-cell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I), or a pharmaceuticallyacceptable salt, hydrate, solvate, prodrug, stereoisomer, or tautomerthereof and a pharmaceutically acceptable carrier. The pharmaceuticalacceptable carrier may further include an excipient, diluent, orsurfactant.

Another aspect of the present invention relates to a compound of Formula(I), or a pharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof, for use in the manufacture of amedicament for treating a disease associated with inhibiting PI5P4K.

Another aspect of the present invention relates to the use of a compoundof Formula (I), or a pharmaceutically acceptable salt, hydrate, solvate,prodrug, stereoisomer, or tautomer thereof, in the treatment of adisease associated with inhibiting PI5P4K.

The present invention further provides methods of treating a disease ordisorder associated with modulation of PI5P4K including, cancer andmetastasis, neurodegenerative diseases, immunological disorders,diabetes, bone and joint diseases, osteoporosis, arthritis inflammatorydisorders, cardiovascular diseases, ischemic diseases, viral infectionsand diseases, viral infectivity and/or latency, and bacterial infectionsand diseases, comprising administering to a patient suffering from atleast one of said diseases or disorder a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof.

The present invention provides inhibitors of PI5P4K that are therapeuticagents in the treatment of diseases such as cancer and metastasis,neurodegenerative diseases, immunological disorders, diabetes, bone andjoint diseases, osteoporosis, arthritis inflammatory disorders,cardiovascular diseases, ischemic diseases, viral infections anddiseases, viral infectivity and/or latency, and bacterial infections anddiseases.

The present invention further provides compounds and compositions withan improved efficacy and safety profile relative to known PI5P4Kinhibitors. The present disclosure also provides agents with novelmechanisms of action toward PI5P4K enzymes in the treatment of varioustypes of diseases including cancer and metastasis, neurodegenerativediseases, immunological disorders, diabetes, bone and joint diseases,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, viral infectivityand/or latency, and bacterial infections and diseases. Ultimately thepresent invention provides the medical community with a novelpharmacological strategy for the treatment of diseases and disordersassociated with PI5P4K enzymes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds and compositions that arecapable of inhibiting the activity PI5P4K. The invention featuresmethods of treating, preventing or ameliorating a disease or disorder inwhich PI5P4K plays a role by administering to a patient in need thereofa therapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt, hydrate, solvate, prodrug,stereoisomer, or tautomer thereof. The methods of the present inventioncan be used in the treatment of a variety of PI5P4K dependent diseasesand disorders by inhibiting the activity of PI5P4K enzymes. Inhibitionof PI5P4K provides a novel approach to the treatment, prevention, oramelioration of diseases including, but not limited to, cancer andmetastasis, neurodegenerative diseases, immunological disorders,osteoporosis, arthritis inflammatory disorders, cardiovascular diseases,ischemic diseases, viral infections and diseases, and bacterialinfections and diseases.

In a first aspect of the invention, the compounds of Formula (I) aredescribed:

and pharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, and tautomers thereof, wherein A, B, R₁, X₁, X₂, and Ware described herein above.

The details of the invention are set forth in the accompanyingdescription below. Although methods and materials similar or equivalentto those described herein can be used in the practice or testing of thepresent invention, illustrative methods and materials are now described.Other features, objects, and advantages of the invention will beapparent from the description and from the claims. In the specificationand the appended claims, the singular forms also include the pluralunless the context clearly dictates otherwise. Unless defined otherwise,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art to which thisinvention belongs. All patents and publications cited in thisspecification are incorporated herein by reference in their entireties.

Definitions

The articles “a” and “an” are used in this disclosure to refer to one ormore than one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

The term “and/or” is used in this disclosure to mean either “and” or“or” unless indicated otherwise.

The term “optionally substituted” is understood to mean that a givenchemical moiety (e.g., an alkyl group) can (but is not required to) bebonded other substituents (e.g., heteroatoms). For instance, an alkylgroup that is optionally substituted can be a fully saturated alkylchain (i.e., a pure hydrocarbon). Alternatively, the same optionallysubstituted alkyl group can have one or more substituents different fromhydrogen. For instance, it can, at any point along the chain be boundedto a halogen atom, a hydroxyl group, or any other substituent describedherein. Thus the term “optionally substituted” means that a givenchemical moiety has the potential to contain other functional groups,but does not necessarily have any further functional groups. Suitablesubstituents used in the optional substitution of the described groupsinclude, without limitation, halogen, oxo, —OH, —CN, —COOH, —CH₂CN,—O—(C₁-C₆) alkyl, (C₁-C₆) alkyl, (C₁-C₆) alkoxy, (C₁-C₆) haloalkyl,(C₁-C₆) haloalkoxy, —O—(C₂-C₆) alkenyl, —O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆) alkynyl, —OH, —OP(O)(OH)₂, —OC(O)(C₁-C₆) alkyl,—C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆) alkyl, —NH₂, —NH((C₁-C₆) alkyl),—N((C₁-C₆) alkyl)₂, —NHC(O)(C₁-C₆) alkyl, —C(O)NH(C₁-C₆) alkyl,—S(O)₂(C₁-C₆) alkyl, —S(O)NH(C₁-C₆)alkyl, and —S(O)N((C₁-C₆)alkyl)₂. Thesubstituents can themselves be optionally substituted. “Optionallysubstituted” as used herein also refers to substituted or unsubstitutedwhose meaning is described below.

As used herein, the term “substituted” means that the specified group ormoiety bears one or more suitable substituents wherein the substituentsmay connect to the specified group or moiety at one or more positions.For example, an aryl substituted with a cycloalkyl may indicate that thecycloalkyl connects to one atom of the aryl with a bond or by fusingwith the aryl and sharing two or more common atoms.

As used herein, the term “unsubstituted” means that the specified groupbears no substituents.

Unless otherwise specifically defined, the term “aryl” refers to cyclic,aromatic hydrocarbon groups that have 1 to 3 aromatic rings, includingmonocyclic or bicyclic groups such as phenyl, biphenyl or naphthyl.Where containing two aromatic rings (bicyclic, etc.), the aromatic ringsof the aryl group may be joined at a single point (e.g., biphenyl), orfused (e.g., naphthyl). The aryl group may be optionally substituted byone or more substituents, e.g., 1 to 5 substituents, at any point ofattachment. Exemplary substituents include, but are not limited to,

—H, -halogen, —O—(C₁-C₆)alkyl, (C₁-C₆)alkyl, —O—(C₂-C₆)alkenyl,—O—(C₂-C₆) alkynyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, —OH, —OP(O)(OH)₂,—OC(O)(C₁-C₆)alkyl, —C(O)(C₁-C₆) alkyl, —OC(O)O(C₁-C₆)alkyl, —NH₂,—NH((C₁-C₆)alkyl), —N((C₁-C₆)alkyl)₂, —S(O)₂—(C₁-C₆) alkyl,—S(O)NH(C₁-C₆)alkyl, and —S(O)N((C₁-C₆)alkyl)₂. The substituents canthemselves be optionally substituted. Furthermore when containing twofused rings the aryl groups herein defined may have an unsaturated orpartially saturated ring fused with a fully saturated ring. Exemplaryring systems of these aryl groups include, but are not limited to,phenyl, biphenyl, naphthyl, anthracenyl, phenalenyl, phenanthrenyl,indanyl, indenyl, tetrahydronaphthalenyl, tetrahydrobenzoannulenyl, andthe like.

Unless otherwise specifically defined, “heteroaryl” means a monovalentmonocyclic or a polycyclic aromatic radical of 5 to 24 ring atoms,containing one or more ring heteroatoms selected from N, O, S, P, or B,the remaining ring atoms being C. A polycyclic aromatic radical includestwo or more fused rings and may further include two or more spiro-fusedrings, e.g., bicyclic, tricyclic, tetracyclic, and the like. Unlessotherwise specifically defined, “fused” means two rings sharing two ringatoms. Unless otherwise specifically defined, “spiro-fused” means tworings sharing one ring atom. Heteroaryl as herein defined also means abicyclic heteroaromatic group wherein the heteroatom is selected from N,O, S, P, or B. Heteroaryl as herein defined also means a tricyclicheteroaromatic group containing one or more ring heteroatoms selectedfrom N, O, S, P, or B. Heteroaryl as herein defined also means atetracyclic heteroaromatic group containing one or more ring heteroatomsselected from N, O, S, P, or B. The aromatic radical is optionallysubstituted independently with one or more substituents describedherein. Examples include, but are not limited to, furyl, thienyl,pyrrolyl, pyridyl, pyrazolyl, pyrimidinyl, imidazolyl, isoxazolyl,oxazolyl, oxadiazolyl, pyrazinyl, indolyl, thiophen-2-yl, quinolyl,benzopyranyl, isothiazolyl, thiazolyl, thiadiazole, indazole,benzimidazolyl, thieno[3,2-b]thiophene, triazolyl, triazinyl,imidazo[1,2-b]pyrazolyl, furo[2,3-c]pyridinyl, imidazo[1,2-a]pyridinyl,indazolyl, pyrrolo[2,3-c]pyridinyl, pyrrolo[3,2-c]pyridinyl,pyrazolo[3,4-c]pyridinyl, thieno[3,2-c]pyridinyl,thieno[2,3-c]pyridinyl, thieno[2,3-b]pyridinyl, benzothiazolyl, indolyl,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuranyl,benzofuran, chromanyl, thiochromanyl, tetrahydroquinolinyl,dihydrobenzothiazine, quinolinyl, isoquinolinyl, 1,6-naphthyridinyl,benzo[de]isoquinolinyl, pyrido[4,3-b][1,6]naphthyridinyl,thieno[2,3-b]pyrazinyl, quinazolinyl, tetrazolo[1,5-a]pyridinyl,[1,2,4]triazolo[4,3-a]pyridinyl, isoindolyl, pyrrolo[2,3-b]pyridinyl,pyrrolo[3,4-b]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[5,4-b]pyridinyl, pyrrolo[1,2-a]pyrimidinyl, tetrahydropyrrolo[1,2-a]pyrimidinyl, 3,4-dihydro-2H-1-pyrrolo[2,1-b]pyrimidine,dibenzo[b,d] thiophene, pyridin-2-one, furo[3,2-c]pyridinyl,furo[2,3-c]pyridinyl, 1H-pyrido[3,4-b][1,4] thiazinyl, benzooxazolyl,benzoisoxazolyl, furo[2,3-b]pyridinyl, benzothiophenyl,1,5-naphthyridinyl, furo[3,2-b]pyridine,[1,2,4]triazolo[1,5-a]pyridinyl, benzo[1,2,3]triazolyl,imidazo[1,2-a]pyrimidinyl, [1,2,4]triazolo[4,3-b]pyridazinyl,benzo[c][1,2,5]thiadiazolyl, benzo[c][1,2,5]oxadiazole,1,3-dihydro-2H-benzo[d]imidazol-2-one,3,4-dihydro-2H-pyrazolo[1,5-b][1,2]oxazinyl,4,5,6,7-tetrahydropyrazolo[1,5-a]pyridinyl, thiazolo[5,4-d]thiazolyl,imidazo[2,1-b][1,3,4]thiadiazolyl, thieno[2,3-b]pyrrolyl, 3H-indolyl,and derivatives thereof. Furthermore, when containing two or more fusedrings, the heteroaryl groups defined herein may have one or moresaturated or partially unsaturated ring fused with one or more fullyunsaturated ring. In heteroaryl ring systems containing more than twofused rings, a saturated or partially unsaturated ring may further befused with a saturated or partially unsaturated ring described herein.Furthermore, when containing three or more fused rings, the heteroarylgroups defined herein may have one or more saturated or partiallyunsaturated ring spiro-fused. Any saturated or partially unsaturatedring described herein is optionally substituted with one or more oxo.Exemplary ring systems of these heteroaryl groups include, for example,indolinyl, indolinonyl, dihydrobenzothiophenyl, dihydrobenzofuran,chromanyl, thiochromanyl, tetrahydroquinolinyl, dihydrobenzothiazine,3,4-dihydro-1H-isoquinolinyl, 2,3-dihydrobenzofuranyl, benzofuranonyl,indolinyl, oxindolyl, indolyl,1,6-dihydro-7H-pyrazolo[3,4-c]pyridin-7-onyl,7,8-dihydro-6H-pyrido[3,2-b]pyrrolizinyl, 8H-pyrido[3,2-b]pyrrolizinyl,1,5,6,7-tetrahydrocyclopenta[b]pyrazolo[4,3-e]pyridinyl,7,8-dihydro-6H-pyrido[3,2-b]pyrrolizine,pyrazolo[1,5-a]pyrimidin-7(4H)-only,3,4-dihydropyrazino[1,2-a]indol-1(2H)-onyl,benzo[c][1,2]oxaborol-1(3H)-olyl,6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]puyrrolo[1,2-d][1,4]oxazin-9-onyl,or6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-onyl.

Halogen or “halo” refers to fluorine, chlorine, bromine, or iodine.

Alkyl refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms. Examples of a (C₁-C₆) alkyl group include,but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl,isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, neopentyl, andisohexyl.

“Alkoxy” refers to a straight or branched chain saturated hydrocarboncontaining 1-12 carbon atoms containing a terminal “O” in the chain,i.e., —O(alkyl). Examples of alkoxy groups include without limitation,methoxy, ethoxy, propoxy, butoxy, t-butoxy, or pentoxy groups.

“Alkenyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkenyl” group contains at least onedouble bond in the chain. The double bond of an alkenyl group can beunconjugated or conjugated to another unsaturated group. Examples ofalkenyl groups include ethenyl, propenyl, n-butenyl, iso-butenyl,pentenyl, or hexenyl. An alkenyl group can be unsubstituted orsubstituted. Alkenyl, as herein defined, may be straight or branched.

“Alkynyl” refers to a straight or branched chain unsaturated hydrocarboncontaining 2-12 carbon atoms. The “alkynyl” group contains at least onetriple bond in the chain. Examples of alkenyl groups include ethynyl,propargyl, n-butynyl, iso-butynyl, pentynyl, or hexynyl. An alkynylgroup can be unsubstituted or substituted.

The term “alkylene” or “alkylenyl” refers to a divalent alkyl radical.Any of the above mentioned monovalent alkyl groups may be an alkylene byabstraction of a second hydrogen atom from the alkyl. As herein defined,alkylene may also be a C₁-C₆ alkylene. An alkylene may further be aC₁-C₄ alkylene. Typical alkylene groups include, but are not limited to,—CH₂—, —CH(CH₃)—, —C(CH₃)₂—, —CH₂CH₂—, —CH₂CH(CH₃)—, —CH₂C(CH₃)₂—,—CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and the like.

“Cycloalkyl” means monocyclic saturated carbon rings containing 3-18carbon atoms. Examples of cycloalkyl groups include, withoutlimitations, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptanyl, cyclooctanyl, norbomyl, norborenyl,bicyclo[2.2.2]octanyl, or bicyclo[2.2.2]octenyl.

“Cycloalkylalkyl” means monocyclic saturated carbon rings containing3-24 carbon atoms further substituted with (C₁-C₆) alkyl groups. Ingeneral cycloalkylalkyl groups herein described display the followingformula

where m is an integer from 1 to 6 and n is an integer from 1 to 16. Thecycloalkyl ring or carbocycle may be optionally substituted by one ormore substituents, e.g., 1 to 5 substituents, at any point ofattachment. The substituents can themselves be optionally substituted.Examples of cycloalkyl groups include, without limitations, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptanyl, cyclooctanyl,norbornyl, norborenyl, bicyclo[2.2.2]octanyl, bicyclo[2.2.2]octenyl,decahydronaphthalenyl, octahydro-TH-indenyl, cyclopentenyl,cyclohexenyl, cyclohexa-1,4-dienyl, cyclohexa-1,3-dienyl,1,2,3,4-tetrahydronaphthalenyl, octahydropentalenyl,3a,4,5,6,7,7a-hexahydro-1H-indenyl, 1,2,3,3a-tetrahydropentalenyl,bicyclo[3.1.0]hexanyl, bicyclo[2.1.0]pentanyl, spiro[3.3]heptanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.1]hept-2-enyl,bicyclo[2.2.2]octanyl, 6-methylbicyclo[3.1.1]heptanyl,2,6,6-trimethylbicyclo[3.1.1]heptanyl, and derivatives thereof.

“Heterocyclyl” or “heterocycloalkyl” monocyclic rings contain carbon andone or more heteroatoms selected from N, O, S, P, or B and wherein therings are not aromatic. The heterocycloalkyl ring structure may besubstituted by one or more substituents. The substituents can themselvesbe optionally substituted. Examples of heterocyclyl rings include, butare not limited to, oxetanyl, azetidinyl, tetrahydrofuranyl,tetrahydropyranyl, pyrrolidinyl, oxazolinyl, oxazolidinyl, thiazolinyl,thiazolidinyl, pyranyl, thiopyranyl, tetrahydropyranyl, dioxalinyl,piperidinyl, morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,thiomorpholinyl S-dioxide, piperazinyl, azepinyl, oxepinyl, diazepinyl,tropanyl, oxazolidinonyl, and homotropanyl.

The term “aromatic” means a planar ring having 4n+2 electrons in aconjugated system. As used herein, “conjugated system” means a system ofconnected p-orbitals with delocalized electrons, and the system mayinclude lone electron pairs.

The term “hydroxyalkyl” means an alkyl group as defined above, where thealkyl group is substituted with one or more OH groups. Examples ofhydroxyalkyl groups include HO—CH₂—, HO—CH₂—CH₂— and CH₃—CH(OH)—.

The term “haloalkyl” as used herein refers to an alkyl group, as definedherein, which is substituted one or more halogen. Examples of haloalkylgroups include, but are not limited to, trifluoromethyl, difluoromethyl,pentafluoroethyl, trichloromethyl, etc.

The term “haloalkoxy” as used herein refers to an alkoxy group, asdefined herein, which is substituted one or more halogen. Examples ofhaloalkyl groups include, but are not limited to, trifluoromethoxy,difluoromethoxy, pentafluoroethoxy, trichloromethoxy, etc.

The term “cyano” as used herein means a substituent having a carbon atomjoined to a nitrogen atom by a triple bond, i.e., C≡N.

The term “amine” as used herein refers to primary (R—NH₂, R≠H),secondary (R₂—NH, R₂≠H) and tertiary (R₃—N, R≠H) amines. A substitutedamine is intended to mean an amine where at least one of the hydrogenatoms has been replaced by the substituent.

The term “amino” as used herein means a substituent containing at leastone nitrogen atom. Specifically, —NH₂, —NH(alkyl) or alkylamino,—N(alkyl)₂ or dialkylamino, amide-, carbamide-, urea, and sulfamidesubstituents are included in the term “amino”.

The term “dialkylamino” as used herein refers to an amino or —NH₂ groupwhere both of the hydrogens have been replaced with alkyl groups, asdefined herein above, i.e., —N(alkyl)₂. The alkyl groups on the aminogroup can be the same or different alkyl groups. Example of alkylaminogroups include, but are not limited to, dimethylamino (i.e., —N(CH₃)₂),diethylamino, dipropylamino, diisopropylamino, di-n-butylamino,di-sec-butylamino, di-tert-butylamino, methyl(ethyl)amino,methyl(butylamino), etc.

“Spirocycloalkyl” or “spirocyclyl” means carbogenic bicyclic ringsystems with both rings connected through a single atom. The ring can bedifferent in size and nature, or identical in size and nature. Examplesinclude spiropentane, spriohexane, spiroheptane, spirooctane,spirononane, or spirodecane. One or both of the rings in a spirocyclecan be fused to another ring carbocyclic, heterocyclic, aromatic, orheteroaromatic ring. One or more of the carbon atoms in the spirocyclecan be substituted with a heteroatom (e.g., O, N, S, or P). A (C₃-C₁₂)spirocycloalkyl is a spirocycle containing between 3 and 12 carbonatoms. One or more of the carbon atoms can be substituted with aheteroatom.

The term “spiroheterocycloalkyl” or “spiroheterocyclyl” is understood tomean a spirocycle wherein at least one of the rings is a heterocycle(e.g., at least one of the rings is furanyl, morpholinyl, orpiperidinyl).

The term “solvate” refers to a complex of variable stoichiometry formedby a solute and solvent. Such solvents for the purpose of the inventionmay not interfere with the biological activity of the solute. Examplesof suitable solvents include, but are not limited to, water, MeOH, EtOH,and AcOH. Solvates wherein water is the solvent molecule are typicallyreferred to as hydrates. Hydrates include compositions containingstoichiometric amounts of water, as well as compositions containingvariable amounts of water.

The term “isomer” refers to compounds that have the same composition andmolecular weight but differ in physical and/or chemical properties. Thestructural difference may be in constitution (geometric isomers) or inthe ability to rotate the plane of polarized light (stereoisomers). Withregard to stereoisomers, the compounds of Formula (I) may have one ormore asymmetric carbon atom and may occur as racemates, racemic mixturesand as individual enantiomers or diastereomers.

The present invention also contemplates isotopically-labelled compoundsof Formula I (e.g., those labeled with ²H and ¹⁴C). Deuterated (i.e., ²Hor D) and carbon-14 (i.e., ¹⁴C) isotopes are particularly preferred fortheir ease of preparation and detectability. Further, substitution withheavier isotopes such as deuterium may afford certain therapeuticadvantages resulting from greater metabolic stability (e.g., increasedin vivo half-life or reduced dosage requirements) and hence may bepreferred in some circumstances. Isotopically labelled compounds ofFormula I can generally be prepared by following procedures analogous tothose disclosed in the Schemes and/or in the Examples herein below, bysubstituting an appropriate isotopically labelled reagent for anon-isotopically labelled reagent.

The disclosure also includes pharmaceutical compositions comprising aneffective amount of a disclosed compound and a pharmaceuticallyacceptable carrier. Representative “pharmaceutically acceptable salts”include, e.g., water-soluble and water-insoluble salts, such as theacetate, amsonate (4,4-diaminostilbene-2,2-disulfonate),benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate,bromide, butyrate, calcium, calcium edetate, camsylate, carbonate,chloride, citrate, clavulariate, dihydrochloride, edetate, edisylate,estolate, esylate, fumarate, gluceptate, gluconate, glutamate,glycollylarsanilate, hexafluorophosphate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate,lactate, lactobionate, laurate, magnesium, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt,3-hydroxy-2-naphthoate, oleate, oxalate, palmitate, pamoate,pantothenate, phosphate/diphosphate, picrate, polygalacturonate,propionate, p-toluenesulfonate, salicylate, stearate, subacetate,succinate, sulfate, sulfosalicylate, tannate, tartrate, teoclate,tosylate, triethiodide, and valerate salts.

A “patient” or “subject” is a mammal, e.g., a human, mouse, rat, guineapig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey,chimpanzee, baboon or rhesus.

An “effective amount” when used in connection with a compound is anamount effective for treating or preventing a disease in a subject asdescribed herein.

The term “carrier”, as used in this disclosure, encompasses carriers,excipients, and diluents and means a material, composition or vehicle,such as a liquid or solid filler, diluent, excipient, solvent orencapsulating material, involved in carrying or transporting apharmaceutical agent from one organ, or portion of the body, to anotherorgan, or portion of the body of a subject.

The term “treating” with regard to a subject, refers to improving atleast one symptom of the subject's disorder. Treating includes curing,improving, or at least partially ameliorating the disorder.

The term “disorder” is used in this disclosure to mean, and is usedinterchangeably with, the terms disease, condition, or illness, unlessotherwise indicated.

The term “administer”, “administering”, or “administration” as used inthis disclosure refers to either directly administering a disclosedcompound or pharmaceutically acceptable salt of the disclosed compoundor a composition to a subject, or administering a prodrug derivative oranalog of the compound or pharmaceutically acceptable salt of thecompound or composition to the subject, which can form an equivalentamount of active compound within the subject's body.

The term “prodrug,” as used in this disclosure, means a compound whichis convertible in vivo by metabolic means (e.g., by hydrolysis) to adisclosed compound.

The present invention relates to compounds or pharmaceuticallyacceptable salts, hydrates, solvates, prodrugs, stereoisomers, ortautomers thereof, capable of inhibiting PI5P4K, which are useful forthe treatment of diseases and disorders associated with modulation of aPI5P4K enzyme. The invention further relates to compounds, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, which are useful for inhibitingPI5P4K.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ia):

wherein:

-   -   represents an optional double bond.

In one embodiment, the compounds of Formula (I) have the structure ofFormula (Ib):

-   -   wherein        represents an optional double bond conferring partial        unsaturation or aromaticity to the ring.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ic):

-   -   wherein Y is C(R₅) or N.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Id):

wherein

-   -   a, b, c, and d, are each independently C or N, wherein at least        one of a, b, c, and d is N, and no more than two of a, b, c, and        d, are N;    -   X₃ and Y₃ are each independently —O—, —CH₂—, or —N(R₈)—;    -   ρ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ie):

wherein:

-   -   represents an optional double bond;    -   a, b, c, and d, are each independently C or N, wherein at least        one of a, b, c, and d is N; and no more than two of a, b, c, d,        and e, are N;    -   X₄ and Z₁ are each independently —O—, —N(R₁₅)—, or        —C(R₁₅)(R₁₅)—; and    -   ω is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (If):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N; and    -   ρ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ig):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N; and    -   λ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ih):

wherein:

-   -   represents an optional double bond;    -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N;    -   Y₄ is —O—, —N(R₁₂)—, or —C(R₁₂)(R₂)—; and    -   Φ is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ii):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N.

In another embodiment, the compounds of Formula (I) have the structureof Formula (IJ):

wherein:

-   -   Y is C(R₅) or N.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ik):

wherein:

-   -   a, b, c, and d, are each independently C or N, wherein at least        one of a, b, c, and d is N, and no more than two of a, b, c, and        d, are N;    -   X₃ and Y₃ are each independently —O—, —CH₂—, or —N(R₈)—;    -   ρ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (II):

wherein:

-   -   represents an optional double bond;    -   a, b, c, and d, are each independently C or N, wherein at least        one of a, b, c, and d is N; and no more than two of a, b, c, d,        and e, are N;    -   X₄ and Z₁ are each independently —O—, —N(R₁₅)—, or        —C(R₁₅)(R₁₅)—; and    -   ω is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Im):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N; and    -   ρ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (In):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N; and    -   λ is 1, 2, or 3.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Io):

wherein:

-   -   represents an optional double bond;    -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N;    -   Y₄ is —O—, —N(R₁₂)—, or —C(R₁₂)(R₁₂)—; and    -   Φ is 0, 1, or 2.

In another embodiment, the compounds of Formula (I) have the structureof Formula (Ip):

wherein:

-   -   a, b, c, d, and e, are each independently C or N, wherein at        least one of a, b, c, d, and e is N, and no more than two of a,        b, c, d, and e, are N.

In some embodiments of the compounds of Formula I, R₁ is —N(R₂)C(O)R₃,—C(O)N(R₂)(R₃), —S(O)₂N(R₂)(R₃), —N(R₂)S(O)₂R₃, or heteroaryl, whereinheteroaryl is optionally substituted with R₇. In another embodiment R₁is —N(R₂)C(O)R₃, —C(O)N(R₂)(R₃), —S(O)₂N(R₂)(R₃), —N(R₂)S(O)₂R₃, orheteroaryl. In another embodiment, R₁ is —N(R₂)C(O)R₃, —C(O)N(R₂)(R₃),—S(O)₂N(R₂)(R₃), or —N(R₂)S(O)₂R₃. In another embodiment, R₁ is—N(R₂)C(O)R₃, —C(O)N(R₂)(R₃), or —S(O)₂N(R₂)(R₃). In another embodiment,R₁ is —N(R₂)C(O)R₃ or —C(O)N(R₂)(R₃). In another embodiment, R₁ is—N(R₂)C(O)R₃. In another embodiment, R₁ is —C(O)N(R₂)(R₃). In anotherembodiment, R₁ is —S(O)₂N(R₂)(R₃). In another embodiment, R₁ is—N(R₂)S(O)₂R₃. In another embodiment, R₁ is heteroaryl. In anotherembodiment, R₁ is heteroaryl, wherein heteroaryl is optionallysubstituted with R₇.

In some embodiments of the compounds of Formula I, W is C(R₆) or N. Inanother embodiment, W is C(R₆). In another embodiment, W is N.

In some embodiments of the compounds of Formula I, A is C₃₋₈ cycloalkyl,C₄₋₈ cycloalkenyl, C₂₋₆ alkynyl, aryl, spiroheterocyclyl, heterocyclyl,or 6-membered heteroaryl. In another embodiment, A is C₃₋₈ cycloalkyl,C₄₋₈ cycloalkenyl, C₂₋₆ alkynyl, aryl, heterocyclyl, or 6-memberedheteroaryl. In another embodiment, A is C₃₋₈ cycloalkyl, C₄₋₈cycloalkenyl, C₂₋₆ alkynyl, aryl, or heterocyclyl. In anotherembodiment, A is C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, C₂₋₆ alkynyl, oraryl. In another embodiment, A is C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, orC₂₋₆ alkynyl. In another embodiment, A is C₃₋₈ cycloalkyl or C₄₋₈cycloalkenyl. In another embodiment, A is C₃₋₈ cycloalkyl. In anotherembodiment, A is C₄₋₈ cycloalkenyl. In another embodiment, A is C₂₋₆alkynyl. In another embodiment, A is spiroheterocyclyl. In anotherembodiment, A is aryl. In another embodiment, A is heterocyclyl. Inanother embodiment, A is 6-membered heteroaryl. In another embodiment, Ais C₃₋₈ cycloalkyl optionally substituted with one or more R₅. Inanother embodiment, A is C₄₋₈ cycloalkenyl optionally substituted withone or more R₅. In another embodiment, A is C₂₋₆ alkynyl optionallysubstituted with one or more R₅. In another embodiment, A isspiroheterocyclyl optionally substituted with one or more R₅. In anotherembodiment, A is aryl optionally substituted with one or more R₅. Inanother embodiment, A is heterocyclyl optionally substituted with one ormore R₅. In another embodiment, A is 6-membered heteroaryl optionallysubstituted with one or more R₅.

In some embodiments of the compounds of Formula I, B is heterocyclyl orheteroaryl. In one embodiment, B is heterocyclyl. In one embodiment, Bis heteroaryl. In one embodiment, B is heterocyclyl optionallysubstituted with one or more R₇. In one embodiment, B is heteroaryloptionally substituted with one or more R₅.

In some embodiments of the compounds of Formula I, X₁ is C(R₅). In oneembodiment, X₁ is C(R₅).

In some embodiments of the compounds of Formula I, X₂ is C(R₅) or N. Inone embodiment, X₂ is C(R₅). In one embodiment, X₂ is N.

In some embodiments of the compounds of Formula I, R₂ is C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl. In another embodiment, R₂ is C₁₋₆ alkyl.In another embodiment, R₂ is C₂₋₆ alkenyl. In another embodiment, R₂ isC₂₋₆ alkynyl. In another embodiment, R₂ is C₁₋₆ alkyl optionallysubstituted with one or more R₄. In another embodiment, R₂ is C₂₋₆alkenyl optionally substituted with one or more R₄. In anotherembodiment, R₂ is C₂₋₆alkynyl optionally substituted with one or moreR₄.

In some embodiments of the compounds of Formula I, R₃ is —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl. In another embodiment, R₃ is —H. Inanother embodiment, R₃ is C₁₋₆ alkyl. In another embodiment, R₃ is C₂₋₆alkenyl. In another embodiment, R₃ is C₂₋₆ alkynyl. In anotherembodiment, R₃ is C₁₋₆ alkyl optionally substituted with one or more R₄.In another embodiment, R₃ is C₂₋₆ alkenyl optionally substituted withone or more R₄. In another embodiment, R₃ is C₂₋₆ alkynyl optionallysubstituted with one or more R₄.

In other embodiments of the compounds of Formula I, R₂ and R₃ when takentogether with the atom to which they are attached form a heterocycle. Inanother embodiment, R₂ and R₃ when taken together with the atom to whichthey are attached form a heterocycle optionally substituted with one ormore R₄.

In other embodiments of the compounds of Formula I, R₄ is —H, halogen,—OH, —NH₂, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein heterocyclyl is optionallysubstituted with one or more R₇. In another embodiment, R₄ is —H,halogen, —OH, —NH₂, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, or aryl. In another embodiment, R₄ is —H, halogen, —OH,—NH₂, —NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, orheterocyclyl. In another embodiment, R₄ is —H, halogen, —OH, —NH₂, —NO₂,—CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₃₋₈ cycloalkyl. In another embodiment,R₄ is —H, halogen, —OH, —NH₂, —NO₂, —CN, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Inanother embodiment, R₄ is —H, halogen, —OH, —NH₂, —NO₂, —CN, or C₁₋₆alkyl. In another embodiment, R₄ is —H, halogen, —OH, —NH₂, —NO₂, or—CN. In another embodiment, R₄ is —H, halogen, —OH, —NH₂, or —NO₂. Inanother embodiment, R₄ is —H, halogen, —OH, or —NH₂. In anotherembodiment, R₄ is —H, halogen, or —OH. In another embodiment, R₄ is —Hor halogen. In another embodiment, R₄ is —H. In another embodiment, R₄is halogen. In another embodiment, R₄ is —OH. In another embodiment, R₄is —NH₂. In another embodiment, R₄ is —NO₂. In another embodiment, R₄ is—CN. In another embodiment, R₄ is C₁₋₆ alkyl. In another embodiment, R₄is C₁₋₆ alkoxy. In another embodiment, R₄ is C₃₋₈ cycloalkyl. In anotherembodiment, R₄ is heterocyclyl. In another embodiment, R₄ is aryl. Inanother embodiment, R₄ is heteroaryl. In another embodiment, R₄ isheterocyclyl optionally substituted with R₇. In another embodiment, R₄is alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl isoptionally substituted with one or more R₇. In another embodiment, R₄ isalkyl optionally substituted with one or more R₇. In another embodiment,R₄ is alkoxy substituted with one or more R₇. In another embodiment, R₄is cycloalkyl optionally substituted with one or more R₇. In anotherembodiment, R₄ is aryl optionally substituted with one or more R₇. Inanother embodiment, R₄ is heteroaryl optionally substituted with one ormore R₇.

In other embodiments of the compounds of Formula I, R₅ is —H, halogen,—OH, —CN, C₁₋₆ alkyl, methoxy, —OC₃-C₆ alkyl, C₃₋₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl. In another embodiment, R₅ is —H,halogen, —OH, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, or aryl. In another embodiment, R₅ is —H, halogen, —OH,—NO₂, —CN, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, or heterocyclyl. Inanother embodiment, R₅ is —H, halogen, —OH, —CN, C₁₋₆ alkyl, C₁₋₆alkoxy, or C₃₋₈ cycloalkyl. In another embodiment, R₅ is —H, halogen,—OH, —CN, C₁₋₆ alkyl, or C₁₋₆ alkoxy. In another embodiment, R₅ is —H,halogen, —OH, —CN, or C₁₋₆ alkyl. In another embodiment, R₅ is —H,halogen, —OH, or —CN. In another embodiment, R₅ is —H, halogen, or —NO₂.In another embodiment, R₅ is —H, halogen, or —OH. In another embodiment,R₅ is —H, halogen, or —OH. In another embodiment, R₅ is —H or halogen.In another embodiment, R₅ is —H. In another embodiment, R₅ is halogen.In another embodiment, R₅ is —OH. In another embodiment, R₅ is —CN. Inanother embodiment, R₅ is C₁₋₆ alkyl. In another embodiment, R₅ is C₁₋₆alkoxy. In another embodiment, R₅ is C₃₋₈ cycloalkyl. In anotherembodiment, R₅ is heterocyclyl. In another embodiment, R₅ is aryl. Inanother embodiment, R₅ is heteroaryl.

In other embodiments of the compounds of Formula I, R₆ is —H, halogen,—OH, —NH₂, —NO₂, —CN, —CO₂H, —C(O)NH₂, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, —O—C₃₋₈ cycloalkyl, or C₁₋₆ alkyl. In other embodiments ofthe compounds of Formula I, R₆ is C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, —O—C₃₋₈ cycloalkyl, or C₁₋₆ alkyl, wherein the alkyl,alkoxy, heterocyclyl, or cycloalkyl is optionally substituted with oneor more —OH, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, —NH₂, —NH(C₁₋₆ alkyl), or—N(C₁₋₆ alkyl)₂. In other embodiments of the compounds of Formula I, R₆is —H, halogen, —OH, —NH₂, —NO₂, —CN, —CO₂H, —C(O)NH₂, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, or C₁₋₆ alkyl. In other embodiments of the compounds ofFormula I, R₆ is —H, halogen, —OH, —NH₂, —NO₂, —CN, —CO₂H, —C(O)NH₂, orC₁₋₆ alkyl. In another embodiment, R₆ is —H, halogen, —OH, —NH₂, —NO₂,—CN, —CO₂H, or —C(O)NH₂. In another embodiment, R₆ is H, halogen, —OH,NH₂, NO₂, CN, or —CO₂H. In another embodiment, R₆ is H, halogen, —OH,NH₂, NO₂, or CN. In another embodiment, R₅ is H, halogen, —OH, NH₂, orNO₂. In another embodiment, R₆ is H, halogen, —OH, or NH₂. In anotherembodiment, R₆ is H, halogen, or —OH. In another embodiment, R₆ is H orhalogen. In another embodiment, R₆ is H. In another embodiment, R₆ ishalogen. In another embodiment, R₆ is —OH. In another embodiment, R₆ isNH₂. In another embodiment, R₆ is NO₂. In another embodiment, R₆ is CN.In another embodiment, R₆ is C₁₋₆ alkyl. In another embodiment, R₆ is—CO₂H. In another embodiment, R₆ is —C(O)NH₂. In another embodiment, R₆is C₁₋₆ alkyl substituted with —OH. In another embodiment, R₆ is C₁₋₆alkyl substituted with C₁₋₆ alkoxy. In another embodiment, R₆ is C₁₋₆alkyl substituted with C₁₋₆ cycloalkyl. In another embodiment, R₆ isC₁₋₆ alkyl is substituted with —NH₂. In another embodiment, R₆ is C₁₋₆alkyl is substituted with —NH(C₁₋₆ alkyl). In another embodiment, R₆ isC₁₋₆ alkyl is substituted with —N(C₁₋₆ alkyl)₂. In another embodiment,R₆ is C₁₋₆ alkoxy substituted with —OH. In another embodiment, R₆ isC₁₋₆ alkoxy substituted with C₁₋₆ alkoxy. In another embodiment, R₆ isC₁₋₆ alkoxy substituted with C₁₋₆ cycloalkyl. In another embodiment, R₆is C₁₋₆ alkoxy is substituted with —NH₂. In another embodiment, R₆ isC₁₋₆ alkoxy is substituted with —NH(C₁₋₆ alkyl). In another embodiment,R₆ is C₁₋₆ alkoxy is substituted with —N(C₁₋₆ alkyl)₂. In anotherembodiment, R₆ is heterocyclyl substituted with —OH. In anotherembodiment, R₆ is heterocyclyl substituted with C₁₋₆ alkoxy. In anotherembodiment, R₆ is heterocyclyl substituted with C₁₋₆ cycloalkyl. Inanother embodiment, R₆ is heterocyclyl is substituted with —NH₂. Inanother embodiment, R₆ is heterocyclyl is substituted with —NH(C₁₋₆alkyl). In another embodiment, R₆ is heterocyclyl is substituted with—N(C₁₋₆ alkyl)₂. In another embodiment, R₆ is cycloalkyl substitutedwith —OH. In another embodiment, R₆ is cycloalkyl substituted with C₁₋₆alkoxy. In another embodiment, R₆ is cycloalkyl substituted with C₁₋₆cycloalkyl. In another embodiment, R₆ is cycloalkyl is substituted with—NH₂. In another embodiment, R₆ is cycloalkyl is substituted with—NH(C₁₋₆ alkyl). In another embodiment, R₆ is cycloalkyl is substitutedwith —N(C₁₋₆ alkyl)₂.

In other embodiments of the compounds of Formula I, R₅ and R₆ when onadjacent carbons and when taken together with the carbon atom to whichthey are each attached form a 5- to 6-membered heteroaryl ring. Inanother embodiment, R₅ and R₆ when on adjacent carbons and when takentogether with the carbon atom to which they are each attached form a5-membered heteroaryl ring. In another embodiment, R₅ and R₆ when onadjacent carbons and when taken together with the carbon atom to whichthey are each attached form a 6-membered heteroaryl ring.

In other embodiments of the compounds of Formula I, R₇ is —H, halogen,—OH, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl,or heteroaryl. In another embodiment, R₇ is —H, halogen, —OH, oxo, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, or aryl. In anotherembodiment, R₇ is —H, halogen, —OH, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, or heterocyclyl. In another embodiment, R₇ is —H, halogen,—OH, oxo, C₁₋₆ alkyl, C₁₋₆ alkoxy, or C₃₋₈ cycloalkyl. In anotherembodiment, R₇ is —H, halogen, —OH, oxo, C₁₋₆ alkyl, or C₁₋₆ alkoxy. Inanother embodiment, R₇ is —H, halogen, —OH, oxo, or C₁₋₆ alkyl. Inanother embodiment, R₇ is —H, halogen, —OH, or oxo. In anotherembodiment, R₇ is —H, halogen, —OH, or oxo. In another embodiment, R₇ is—H, halogen, or —OH. In another embodiment, R₇ is —H or halogen. Inanother embodiment, R₇ is —H. In another embodiment, R₇ is halogen. Inanother embodiment, R₇ is —OH. In another embodiment, R₇ is oxo. Inanother embodiment, R₇ is C₁₋₆ alkyl. In another embodiment, R₇ is C₁₋₆alkoxy. In another embodiment, R₇ is C₃₋₈ cycloalkyl. In anotherembodiment, R₇ is heterocyclyl. In another embodiment, R₇ is aryl. Inanother embodiment, R₇ is heteroaryl. In another embodiment, R₇ is C₁₋₆alkyl optionally substituted with one or more R₁₄. In anotherembodiment, R₇ is C₁₋₆ alkoxy optionally substituted with one or moreR₁₄. In another embodiment, R₇ is C₃₋₈ cycloalkyl optionally substitutedwith one or more R₁₄. In another embodiment, R₇ is heterocyclyloptionally substituted with one or more R₁₄. In another embodiment, R₇is aryl optionally substituted with one or more R₁₄. In anotherembodiment, R₇ is heteroaryl optionally substituted with one or moreR₁₄.

In other embodiments of the compounds of Formula I, R₅ is H, —CN, oxo,C₁₋₆ alkyl, heterocyclyl, aryl, heteroaryl —N(R₉)C(O)R₁₀,—N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀,C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀). In anotherembodiment, R₅ is H. In another embodiment, R₅ is —CN. In anotherembodiment, R₅ is oxo. In another embodiment, R₅ is C₁₋₆ alkyl. Inanother embodiment, R₅ is heterocyclyl. In another embodiment, R₅ isaryl. In another embodiment, R₅ is heteroaryl. In another embodiment, R₅is —N(R₉)C(O)R₁₀. In another embodiment, R₅ is —N(R₉)C(O)OR₁₀. Inanother embodiment, R₅ is —N(R₉)C(O)N(R₉)(R₁₀). In another embodiment,R₅ is —N(R₉)S(O)₂R₁₀. In another embodiment, R₅ is —S(O)₂R₁₀. In anotherembodiment, R₅ is C(O)R₉. In another embodiment, R₅ is —N(R₉)(R₁₀). Inanother embodiment, R₅ is —OR₁₀. In another embodiment, R₅ is—N(R₉)C(O)R₁₃. In another embodiment, R₅ is —C(O)N(R₉)(R₁₀). In anotherembodiment, R₅ is C₁₋₆ alkyl optionally substituted with one or moreR₁₅. In another embodiment, R₅ is C₃₋₈ cycloalkyl optionally substitutedwith one or more R₁₅. In another embodiment, R₅ is heterocyclyloptionally substituted with one or more R₁₅. In another embodiment, R₅is aryl optionally substituted with one or more R₁₅. In anotherembodiment, R₅ is heteroaryl optionally substituted with one or moreR₁₅.

In other embodiments of the compounds of Formula I, R₈ groups, togetherwith the atoms to which they are attached, form a C₃₋₆ cycloalkyl, C₅₋₆spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl, aryl, orheteroaryl. In some embodiments, R₈ groups, together with the atoms towhich they are attached, form a C₃₋₆ cycloalkyl. In some embodiments, R₈groups, together with the atoms to which they are attached, form a C₅₋₆spirocycloalkyl. In some embodiments, R₈ groups, together with the atomsto which they are attached, form a spiroheterocycloalkyl. In someembodiments, R₈ groups, together with the atoms to which they areattached, form a heterocyclyl. In some embodiments, R₈ groups, togetherwith the atoms to which they are attached, form an aryl. In someembodiments, R₈ groups, together with the atoms to which they areattached, form a heteroaryl. In some embodiments, R₈ groups, togetherwith the atoms to which they are attached, form a C₃₋₆ cycloalkyloptionally substituted with one or more R₁₅. In some embodiments, R₈groups, together with the atoms to which they are attached, form a C₅₋₆spirocycloalkyl optionally substituted with one or more R₁₅. In someembodiments, R₈ groups, together with the atoms to which they areattached, form a spiroheterocycloalkyl optionally substituted with oneor more R₁₅. In some embodiments, R₈ groups, together with the atoms towhich they are attached, form a heterocyclyl optionally substituted withone or more R₁₅. In some embodiments, R₈ groups, together with the atomsto which they are attached, form an aryl optionally substituted with oneor more R₂₄. In some embodiments, R₈ groups, together with the atoms towhich they are attached, form a heteroaryl optionally substituted withone or more R₂₄.

In some embodiments of the compounds of Formula I, R₉ is —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, orheterocyclyl. In another embodiment, R₉ is —H. In another embodiment, R₉is C₁₋₆ alkyl. In another embodiment, R₉ is C₂₋₆ alkenyl. In anotherembodiment, R₉ is C₂₋₆ alkynyl. In another embodiment, R₉ is C₃₋₈cycloalkyl. In another embodiment, R₉ is heterocyclyl. In anotherembodiment, R₉ is aryl. In another embodiment, R₉ is heteroaryl. Inanother embodiment, R₉ is C₁₋₆ alkyl optionally substituted with one ormore R₁₁. In another embodiment, R₉ is C₂₋₆ alkenyl optionallysubstituted with one or more R₁₁. In another embodiment, R₉ is C₂₋₆alkynyl optionally substituted with one or more R₁₁. In anotherembodiment, R₉ is C₃₋₈ cycloalkyl optionally substituted with one ormore R₁₁. In another embodiment, R₉ is heterocyclyl optionallysubstituted with one or more R₁₁. In another embodiment, R₉ is aryloptionally substituted with one or more R₁₁. In another embodiment, R₉is heteroaryl optionally substituted with one or more R₁₁.

In some embodiments of the compounds of Formula I, R₁₀ is —H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, aryl, heteroaryl, orheterocyclyl. In another embodiment, R₁₀ is —H. In another embodiment,R₁₀ is C₁₋₆ alkyl. In another embodiment, R₁₀ is C₂₋₆ alkenyl. Inanother embodiment, R₁₀ is C₂₋₆ alkynyl. In another embodiment, R₁₀ isC₃₋₈ cycloalkyl. In another embodiment, R₁₀ is heterocyclyl. In anotherembodiment, R₁₀ is aryl. In another embodiment, R₁₀ is heteroaryl. Inanother embodiment, R₁₀ is C₁₋₆ alkyl optionally substituted with one ormore R₁₁. In another embodiment, R₁₀ is C₂₋₆ alkenyl optionallysubstituted with one or more R₁₁. In another embodiment, R₁₀ is C₂₋₆alkynyl optionally substituted with one or more R₁₁. In anotherembodiment, R₁₀ is C₃₋₈ cycloalkyl optionally substituted with one ormore R₁₁. In another embodiment, R₁₀ is heterocyclyl optionallysubstituted with one or more R₁₁. In another embodiment, R₁₀ is aryloptionally substituted with one or more R₁₁. In another embodiment, R₁₀is heteroaryl optionally substituted with one or more R₁₁.

In other embodiments of the compounds of Formula I, R₉ and R₁₀ whentaken together with the atom to which they are each attached form aheterocycle ring. In another embodiment, R₉ and R₁₀ when taken togetherwith the atom to which they are each attached form a heterocycle ringoptionally substituted with one or more R₁₂.

In other embodiments of the compounds of Formula I, R₁ is —H, halogen,—CN, oxo, —OH, —N(R₂₃)(R₂₅), —OR₂₃, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, aryl, —C(O)R₁₇, —C(O)R₁₇,—C(O)OR₁₇, —OC(O)R₁₇, or —C(O)N(R₂₃)(R₂₃). In another embodiment, R₁ is—H. In another embodiment, R₁ is halogen. In another embodiment, R₁ is—CN. In another embodiment, R₁ is oxo. In another embodiment, R₁ is —OH.In another embodiment, R₁ is —N(R₂₃)(R₂₅). In another embodiment, R₁ is—OR₂₃. In another embodiment, R₁ is C₁₋₆ alkyl. In another embodiment,R₁ is C₁₋₆ alkoxy. In another embodiment, R₁ is C₃₋₈ cycloalkyl. Inanother embodiment, R₁ is heterocyclyl. In another embodiment, R₁ isheteroaryl. In another embodiment, R₁ is aryl. In another embodiment, R₁is —C(O)R₁₇. In another embodiment, R₁ is —C(O)OR₁₇. In anotherembodiment, R₁ is —OC(O)R₁₇. In another embodiment, R₁ is—C(O)N(R₂₃)(R₂₃). In another embodiment, R₁ is C₁₋₆ alkyl optionallysubstituted with one or more R₁₇. In another embodiment, R₁₁ is C₁₋₆alkoxy optionally substituted with one or more R₁₇. In anotherembodiment, R₁₁ is C₃₋₈ cycloalkyl optionally substituted with one ormore R₁₇. In another embodiment, R₁₁ is heterocyclyl optionallysubstituted with one or more R₁₇. In another embodiment, R₁₁ isheteroaryl. In another embodiment, R₁₁ is aryl optionally substitutedwith one or more R₁₇. In another embodiment, R₁₁ is heterocyclyloptionally substituted with one or more R₁₇.

In other embodiments of the compounds of Formula I, each R₁₂ is—C(O)OR₂₁, —C(O)R₁₃; oxo, —OH, C₁₋₆ alkyl, heterocycle, —(C₁₋₆alkyl)-heteroaryl, —(C₁₋₆ alkyl)-heterocycle, —(C₁₋₆alkyl)-C₃₋₆cycloalkyl, or —(C₁₋₆ alkyl)-aryl. In another embodiment, R₁₂ is—C(O)OR₂₁. In another embodiment, R₁₂ is —C(O)R₁₃. In anotherembodiment, R₁₂ is oxo. In another embodiment, R₁₂ is —OH. In anotherembodiment, R₁₂ is C₁₋₆ alkyl. In another embodiment, R₁₂ isheterocycle. In another embodiment, R₁₂ is —(C₁₋₆ alkyl)-heteroaryl. Inanother embodiment, R₁₂ is —(C₁₋₆alkyl)-C₃₋₆ cycloalkyl. In anotherembodiment, R₁₂ is —(C₁₋₆ alkyl)-aryl. In another embodiment, R₁₂ isC₁₋₆ alkyl optionally substituted with one or more R₁₅. In anotherembodiment, R₁₂ is heterocycle optionally substituted with one or moreR₁₅. In another embodiment, R₁₂ is —(C₁₋₆ alkyl)-heteroaryl optionallysubstituted with one or more R₁₁. In another embodiment, R₁₂ is—(C₁₋₆alkyl)-C₃₋₆ cycloalkyl optionally substituted with one or moreR₁₈. In another embodiment, R₁₂ is —(C₁₋₆ alkyl)-aryl optionallysubstituted with one or more R₁₈.

In other embodiments of the compounds of Formula I, two R₁₂ togetherwith the atoms to which they are attached form an aryl ring. In anotherembodiment, two R₁₂ together with the atoms to which they are attachedform an aryl ring optionally substituted with one or more R₁₁.

In some embodiments of the compounds of Formula I, R₁₃ is aryl,heterocyclyl, cycloalkyl, or heteroaryl. In another embodiment, R₁₃ isaryl. In another embodiment, R₁₃ is heterocyclyl. In another embodiment,R₁₃ is C₃₋₈ cycloalkyl. In another embodiment, R₁₃ is heteroaryl. Inanother embodiment, R₁₃ is aryl optionally substituted with one or moreR₁₉. In another embodiment, R₁₃ is heterocyclyl optionally substitutedwith one or more R₂₀. In another embodiment, R₁₃ is C₃₋₈ cycloalkyloptionally substituted with one or more R₂₀. In another embodiment, R₁₃is heteroaryl optionally substituted with one or more R₁₉.

In some embodiments of the compounds of Formula I, R₁₄ is —H, halogen,—CN, —NO₂, —OH, —NH₂, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl,or heteroaryl. In another embodiment, R₁₄ is —H. In another embodiment,R₁₄ is halogen. In another embodiment, R₁₄ is —CN. In anotherembodiment, R₁₄ is NO₂. In another embodiment, R₁₄ is —OH. In anotherembodiment, R₁₄ is —NH₂. In another embodiment, R₁₄ is C₁₋₆alkyl. Inanother embodiment, R₁₄ is C₃₋₈ cycloalkyl. In another embodiment, R₁₄is heterocyclyl. In another embodiment, R₁₄ is aryl. In anotherembodiment, R₁₄ is heteroaryl.

In some embodiments of the compounds of Formula I, R₅ is H, halogen,oxo, —OH, —NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, —N(R₂₃)C(O)—Ar—N(R₂₃)-G, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G. In one embodiment, R₁₅ is H. In oneembodiment, R₁₅ is halogen. In one embodiment, R₁₅ is oxo. In oneembodiment, R₁₅ is —OH. In one embodiment, R₁₅ is —NH₂. In oneembodiment, R₁₅ is —NO₂. In one embodiment, R₁₅ is C₁₋₆ alkyl. In oneembodiment, R₁₅ is C₁₋₆ alkoxy. In one embodiment, R₁₅ is C₃₋₈cycloalkyl. In one embodiment, R₁₅ is heterocyclyl. In one embodiment,R₁₅ is aryl. In one embodiment, R₁₅ is heteroaryl. In one embodiment,R₁₅ is —C(O)N(R₂₁)(R₂₃). In one embodiment, R₅ is —(CH₂)_(o)—C(O)R₂₃. Inone embodiment, R₁₅ is —OC(O)R₂₃. In one embodiment, R₁₅ is —C(O)OR₂₃.In one embodiment, R₁₅ is —SO₂R₂₃. In one embodiment, R₅ is—N(R₂₃)C(O)—Ar—N(R₂₃)-G. In one embodiment, R₁₅ is—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G. In one embodiment, R₁₅ is C₁₋₆ alkyloptionally substituted with one or more R₂₃. In one embodiment, R₁₅ isC₁₋₆ alkoxy optionally substituted with one or more R₂₃. In oneembodiment, R₁₅ is C₃₋₈ cycloalkyl optionally substituted with one ormore R₂₃. In one embodiment, R₁₅ is heterocyclyl optionally substitutedwith one or more R₂₃. In one embodiment, R₁₅ is aryl optionallysubstituted with one or more R₂₃. In one embodiment, R₁₅ is heteroaryloptionally substituted with one or more R₂₃.

In other embodiments of the compounds of Formula I, two R₁₅ groups,together with the atoms to which they are attached, form a C₃₋₆cycloalkyl or C₅₋₆ spirocycloalkyl. In another embodiment, two R₁₅groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl. In another embodiment, two R₁₅ groups, together with theatoms to which they are attached, form a C₅₋₆ spirocycloalkyl. Inanother embodiment, two R₁₅ when on adjacent atoms may be taken togetherwith the atoms to which they are each attached to form a heterocycle. Inanother embodiment, two R₁₅ when on adjacent atoms may be taken togetherwith the atoms to which they are each attached to form a heterocyclesubstituted with one or more R₁₆.

In some embodiments of the compounds of Formula I, Ar is aryl.

In some embodiments of the compounds of Formula I, G is H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, —C(O)OR₂₃, —C(O)CH═CHCH₂N(R₂₃)(R₂₃), or—C(O)N(R₂₁)(R₂₃). In one embodiment, G is H. In one embodiment, G isC₁₋₆ alkyl. In one embodiment, G is C₁₋₆ alkoxy. In one embodiment, G isC₂₋₆ alkenyl. In one embodiment, G is C₂₋₆ alkynyl. In one embodiment, Gis C₃₋₈ cycloalkyl. In one embodiment, G is heterocyclyl. In oneembodiment, G is aryl. In one embodiment, G is heteroaryl. In oneembodiment, G is —C(O)OR₂₃. In one embodiment, G is—C(O)CH═CHCH₂N(R₂₃)(R₂₃). In one embodiment, G is —C(O)N(R₂₁)(R₂₃).

In some embodiments of the compounds of Formula I, R₁₆ is C₁₋₆ alkyl,C₃₋₆ cycloalkyl, —C(O)R₂₃, —C(O)OR₂₃, —S(O)₂R₂₃, or oxo. In anotherembodiment, R₁₆ is C₁₋₆ alkyl. In another embodiment, R₁₆ is C₃₋₈cycloalkyl. In another embodiment, R₁₆ is —C(O)R₂₃ In anotherembodiment, R₁₆ is —C(O)OR₂₃. In another embodiment, R₁₆ is —S(O)₂R₂₃.In another embodiment, R₁₆ is oxo.

In some embodiments of the compounds of Formula I, R₁₇ is —H, —CN, C₁₋₆alkyl, C₁₋₆ alkoxy, heteroaryl, aryl, —N(R₂₃)(R₂₃), —N(R₂₃)C(O)OR₂₃,—C(O)N(R₂₃)(R₂₃), —N(R₂₃)C(O) R₂₃, —N(R₂₃)C(O)—U—Z, or—N(R₂₃)C(O)—U—N(R₂₃)—Z. In one embodiment, R₁₇ is —H. In one embodiment,R₁₇ is —CN. In one embodiment, R₁₇ is C₁₋₆ alkyl. In one embodiment, R₁₇is C₁₋₆ alkoxy. In one embodiment, R₁₇ is heteroaryl. In one embodiment,R₁₇ is aryl. In one embodiment, R₁₇ is —N(R₂₃)(R₂₃). In one embodiment,R₁₇ is —N(R₂₃)C(O)OR₂₃. In one embodiment, R₁₇ is —C(O)N(R₂₃)(R₂₃). Inone embodiment, R₁₇ is —N(R₂₃)C(O) R₂₃. In one embodiment, R₁₇ is—N(R₂₃)C(O)—U—Z. In one embodiment, R₁₇ is —N(R₂₃)C(O)—U—N(R₂₃)—Z.

In other embodiments of the compounds of Formula I, Z is —H, C₁₋₆ alkyl,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl,aryl, heteroaryl, or —C(O)—U—N(R₂₃)(R₂₃). In one embodiment, Z is —H. Inone embodiment, Z is C₁₋₆ alkyl. In one embodiment, Z is C₁₋₆ alkoxy. Inone embodiment, Z is C₂₋₆ alkenyl. In one embodiment, Z is C₂₋₆ alkynyl.In one embodiment, Z is C₃₋₈ cycloalkyl. In one embodiment, Z isheterocyclyl. In one embodiment, Z is aryl. In one embodiment, Z isheteroaryl. In one embodiment, Z is —C(O)—U—N(R₂₃)(R₂₃).

In other embodiments of the compounds of Formula I, U is —(CH₂)_(p)—,—(CH₂)_(p)—Ar—, —CH═CH(CH₂)_(p)— or heterocyclyl. In one embodiment, Uis —(CH₂)_(p)—. In one embodiment, U is —(CH₂)_(p)—Ar—. In oneembodiment, U is —CH═CH(CH₂)_(p)—. In one embodiment, U is heterocyclyl.

In some embodiments of the compounds of Formula I, R₁ is C₁₋₆ alkyl,heteroaryl, heterocyclyl, cycloalkyl, aryl, —OR₂₃, —N(R₂₃)(R₂₃), or—N(R₂₃)C(O)—V—N(R₂₃)-E. In another embodiment, R₁₈ is C₁₋₆ alkyl. Inanother embodiment, R₁₈ is heteroaryl. In another embodiment, R₁₈ isheterocyclyl. In another embodiment, R₁₈ is cycloalkyl. In anotherembodiment, R₁₈ is aryl. In another embodiment, R₁₈ is —OR₂₃. In anotherembodiment, R₁₈ is —N(R₂₃)(R₂₃). In another embodiment, R₁₈ is—N(R₂₃)C(O)—V—N(R₂₃)-E. In another embodiment, R₁₈ is C₁₋₆ alkyloptionally substituted with one or more R₁₉. In another embodiment, R₁₈is heteroaryl optionally substituted with one or more R₁₉. In anotherembodiment, R₁₈ is heterocyclyl optionally substituted with one or moreR₁₉. In another embodiment, R₁₈ is cycloalkyl optionally substitutedwith one or more R₁₉. In another embodiment, R₁₈ is aryl optionallysubstituted with one or more R₁₉.

In other embodiments of the compounds of Formula I, V is —(CH₂)_(n)—,—(CH₂)_(n)—Ar—, or —CH═CH(CH₂)_(n)—. In one embodiment, V is—(CH₂)_(n)—. In one embodiment, V is —(CH₂)_(n)—Ar—. In one embodiment,V is —CH═CH(CH₂)_(n)—.

In some embodiments of the compounds of Formula I, E is H, C₁₋₆ alkyl or—C(O)—V—N(R₂₃)(R₂₃). In one embodiment, E is H. In one embodiment, E isC₁₋₆ alkyl. In one embodiment, E is —C(O)—V—N(R₂₃)(R₂₃).

In some embodiments of the compounds of Formula I, R₁₉ is halogen, C₁₋₆alkyl, C₃₋₆ cycloalkyl, —OR₂₁, —N(R₂₁)(R₂₂), —C(O)R₂₁, —N(R₂₃)C(O)OR₂₃,—N(R₂₃)C(O)-Q-N(R₂₃)—F, or —N(R₂₃)-Q-N(R₂₃)—F. In another embodiment,R₁₉ is halogen. In another embodiment, R₁₉ is C₁₋₆ alkyl. In anotherembodiment, R₁₉ is C₃₋₆ cycloalkyl. In another embodiment, R₁₉ is —OR₂₁.In another embodiment, R₁₉ is —N(R₂₁)(R₂₂). In another embodiment, R₁₉is —C(O)R₂₁. In another embodiment, R₁₉ is —N(R₂₃)C(O)OR₂₃. In anotherembodiment, R₁₉ is —N(R₂₃)C(O)-Q-N(R₂₃)—F. In another embodiment, R₁₉ is—N(R₂₃)-Q-N(R₂₃)—F.

In other embodiments of the compounds of Formula I, Q is—CH═CH(CH₂)_(m)—, —(CH₂)_(m)—, —(CH₂O)_(m)—, —(CH₂)_(m)Ar—, or—(CH₂CH₂O)_(o)—(CH₂)_(m)—. In another embodiment, Q is —CH═CH(CH₂)_(m)—.In another embodiment, Q is —(CH₂)_(m)—. In another embodiment, Q is—(CH₂O)_(m)—. In another embodiment, Q is —(CH₂)_(m)Ar—. In anotherembodiment, Q is —(CH₂CH₂O)_(o)—(CH₂)_(m)—.

In other embodiments of the compounds of Formula I, F is H, C₁₋₆ alkyl,aryl, heteroaryl, —C(O)-Q-R₂₃, or —C(O)-Q-N(R₂₃)(R₂₃). In anotherembodiment, F is H. In another embodiment, F is C₁₋₆ alkyl. In anotherembodiment, F is aryl. In another embodiment, F is heteroaryl. Inanother embodiment, F is —C(O)-Q-R₂₃. In another embodiment, F is—C(O)-Q-N(R₂₃)(R₂₃). In another embodiment, F is C₁₋₆ alkyl optionallysubstituted with one or more R₂₃. In another embodiment, F is aryloptionally substituted with one or more R₂₃. In another embodiment, F isheteroaryl optionally substituted with one or more R₂₃.

In some embodiments of the compounds of Formula I, R₂₀ is H, halogen,—OH, —NH₂, oxo, —C(O)R₂₁, —OR₂₃, C₃₋₆ cycloalkyl, or C₁₋₆ alkyl. Inanother embodiment, R₂₀ is —H. In another embodiment, R₂₀ is halogen. Inanother embodiment, R₂₀ is —OH. In another embodiment, R₂₀ is —NH₂. Inanother embodiment, R₂₀ is oxo. In another embodiment, R₂₀ is —C(O)R₂₁.In another embodiment, R₂₀ is —OR₂₃. In another embodiment, R₂₀ is C₃₋₆cycloalkyl. In another embodiment, R₂₀ is C₁₋₆ alkyl.

In some embodiments of the compounds of Formula I, R₂₁ is —H, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl,or heteroaryl. In another embodiment, R₂₁ is —H. In another embodiment,R₂₁ is C₁₋₆ alkyl. In another embodiment, R₂₁ is C₂₋₆ alkenyl. Inanother embodiment, R₂₁ is C₂₋₆ alkynyl. In another embodiment, R₂₁ isC₃₋₈ cycloalkyl. In another embodiment, R₂₁ is heterocyclyl. In anotherembodiment, R₂₁ is aryl. In another embodiment, R₂₁ is heteroaryl. Inanother embodiment, R₂₁ is C₁₋₆ alkyl optionally substituted with one ormore —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₁ is C₂₋₆alkenyl optionally substituted with one or more —H, halogen, —CN, —OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, oraryl. In another embodiment, R₂₁ is C₂₋₆ alkynyl optionally substitutedwith one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment,R₂₁ is C₃₋₈ cycloalkyl optionally substituted with one or more —H,halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₁ isheterocyclyl optionally substituted with one or more —H, halogen, —CN,—OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl,or aryl. In another embodiment, R₂₁ is aryl optionally substituted withone or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment,R₂₁ is heteroaryl optionally substituted with one or more —H, halogen,—CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl,heteroaryl, or aryl.

In other embodiments of the compounds of Formula I, R₂₂ is —H, C₁₋₆alkyl, or —C(O)R₂₃. In one embodiment, R₂₂ is —H. In one embodiment, R₂₂is C₁₋₆ alkyl. In one embodiment, R₂₂ is —C(O)R₂₃.

In other embodiment of the compounds of Formula I, R₂₃ is —H, C₁₋₆alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl. In another embodiment, R₂₃ is —H. Inanother embodiment, R₂₃ is C₁₋₆ alkyl. In another embodiment, R₂₃ isC₁₋₆ alkoxy. In another embodiment, R₂₃ is C₂₋₆ alkenyl. In anotherembodiment, R₂₃ is C₂₋₆ alkynyl. In another embodiment, R₂₃ is C₃₋₈cycloalkyl. In another embodiment, R₂₃ is heterocyclyl. In anotherembodiment, R₂₃ is aryl. In another embodiment, R₂₃ is heteroaryl. Inanother embodiment, R₂₃ is C₁₋₆ alkyl optionally substituted with one ormore —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₃ is C₁₋₆alkoxy optionally substituted with one or more —H, halogen, —CN, —OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, oraryl. In another embodiment, R₂₃ is C₂₋₆ alkenyl optionally substitutedwith one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment,R₂₃ is C₂₋₆ alkynyl optionally substituted with one or more —H, halogen,—CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl,heteroaryl, or aryl. In another embodiment, R₂₃ is C₃₋₈ cycloalkyloptionally substituted with one or more —H, halogen, —CN, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl.In another embodiment, R₂₃ is heterocyclyl optionally substituted withone or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment,R₂₃ is aryl optionally substituted with one or more —H, halogen, —CN,—OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl,or aryl. In another embodiment, R₂₃ is heteroaryl optionally substitutedwith one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl.

In one embodiment of the compounds of Formula I, R₂₄ is —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl,heteroaryl, C(O)N(C₁₋₆ alkyl)(C₁₋₆ alkyl), —C(O)—C₁₋₆ alkyl, —OC(O)—C₁₋₆alkyl or —C(O)O—C₁₋₆ alkyl. In another embodiment, R₂₄ is-H. In anotherembodiment, R₂₄ is C₁₋₆ alkyl. In another embodiment, R₂₄ is C₂₋₆alkenyl. In another embodiment, R₂₄ is C₂₋₆ alkynyl. In anotherembodiment, R₂₄ is C₃₋₈ cycloalkyl. In another embodiment, R₂₄ isheterocyclyl. In another embodiment, R₂₄ is aryl. In another embodiment,R₂₄ is heteroaryl. In another embodiment, R₂₄ is —C(O)N(C₁₋₆ alkyl)(C₁₋₆alkyl). In another embodiment, R₂₄ is —C(O)—C₁₋₆ alkyl. In anotherembodiment, R₂₄ is —OC(O)—C₁₋₆ alkyl. In another embodiment, R₂₄ is—C(O)O—C₁₋₆ alkyl. In another embodiment, R₂₄ is C₁₋₆ alkyl optionallysubstituted with one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl. In anotherembodiment, R₂₄ is C₂₋₆ alkenyl optionally substituted with one or more—H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₄ is C₂₋₆alkynyl optionally substituted with one or more —H, halogen, —CN, —OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl, heterocyclyl, heteroaryl, oraryl. In another embodiment, R₂₄ is C₃₋₈ cycloalkyl optionallysubstituted with one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₈-cycloalkyl, heterocyclyl, heteroaryl, or aryl. In anotherembodiment, R₂₄ is heterocyclyl optionally substituted with one or more—H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₄ is aryloptionally substituted with one or more —H, halogen, —CN, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl.In another embodiment, R₂₄ is heteroaryl optionally substituted with oneor more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₄ isC(O)N(C₁₋₆ alkyl)(C₁₋₆ alkyl) optionally substituted with one or more—H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₄ is—C(O)—C₁₋₆ alkyl optionally substituted with one or more —H, halogen,—CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl, heterocyclyl,heteroaryl, or aryl. In another embodiment, R₂₄ is —OC(O)—C₁₋₆ alkyloptionally substituted with one or more —H, halogen, —CN, —OH, C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl, heterocyclyl, heteroaryl, or aryl.In another embodiment, R₂₄ is —C(O)O—C₁₋₆ alkyl optionally substitutedwith one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₈-cycloalkyl, heterocyclyl, heteroaryl, or aryl.

In other embodiment of the compounds of Formula I, R₂₅ is C₁₋₆ alkyl,C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl. In another embodiment, R₂₅ is C₁₋₆ alkyl. Inanother embodiment, R₂₅ is C₁₋₆ alkoxy. In another embodiment, R₂₅ isC₂₋₆ alkenyl. In another embodiment, R₂₅ is C₂₋₆ alkynyl. In anotherembodiment, R₂₅ is C₃₋₈ cycloalkyl. In another embodiment, R₂₅ isheterocyclyl. In another embodiment, R₂₅ is aryl. In another embodiment,R₂₅ is heteroaryl. In another embodiment, R₂₅ is C₁₋₆ alkyl optionallysubstituted with one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl. In anotherembodiment, R₂₅ is C₁₋₆ alkoxy optionally substituted with one or more—H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₅ is C₂₋₆alkenyl optionally substituted with one or more —H, halogen, —CN, —OH,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, oraryl. In another embodiment, R₂₅ is C₂₋₆ alkynyl optionally substitutedwith one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl. In another embodiment,R₂₅ is C₃₋₈ cycloalkyl optionally substituted with one or more —H,halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, heteroaryl, or aryl. In another embodiment, R₂₅ isheterocyclyl optionally substituted with one or more —H, halogen, —CN,—OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl,or aryl. In another embodiment, R₂₅ is aryl optionally substituted withone or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₈-cycloalkyl, heterocyclyl, heteroaryl, or aryl. In anotherembodiment, R₂₅ is heteroaryl optionally substituted with one or more—H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈-cycloalkyl,heterocyclyl, heteroaryl, or aryl.

In one embodiment, p is 1, 2, 3, or 4. In another embodiment p is 1, 2,or 3. In another embodiment p is 1 or 2. In another embodiment p is 1.In another embodiment p is 2. In another embodiment p is 3. In anotherembodiment p is 4.

In one embodiment, n is 1, 2, 3, or 4. In another embodiment n is 1, 2,or 3. In another embodiment n is 1 or 2. In another embodiment n is 1.In another embodiment n is 2. In another embodiment n is 3. In anotherembodiment n is 4.

In one embodiment, m is 1, 2, 3, or 4. In another embodiment m is 1, 2,or 3. In another embodiment m is 1 or 2. In another embodiment m is 1.In another embodiment m is 2. In another embodiment m is 3. In anotherembodiment m is 4.

In one embodiment, o is 1, 2, or 3. In another embodiment o is 1 or 2.In another embodiment o is 1. In another embodiment o is 2. In anotherembodiment o is 3.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ isheteroaryl.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ isheteroaryl.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), andR₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl optionally substituted with one or more R₇, X₁ isC(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl optionally substituted with one or moreR₇, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅),X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl optionally substituted with one or more R₇, X₁ isC(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl optionally substituted with one or moreR₇, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —S(O)₂N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ isheteroaryl.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is heteroaryl.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)S(O)₂R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl optionally substituted with one or more R₇, X₁ isC(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl optionally substituted with one or moreR₇, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅),X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heterocyclyl optionally substituted with one or more R₇, X₁ isC(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heterocyclyl optionally substituted with one or moreR₇, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheterocyclyl optionally substituted with one or more R₇, X₁ is C(R₅), X₂is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, wherein R₈ is—H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, wherein R₈is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₃, or —C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W isC(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀), X₂ is C(R₅), W is C(R₆), andR₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, wherein R₈ is—H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, wherein R₈is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W isC(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₁₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₈is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, wherein R₈ is—H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, wherein R₈is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W isC(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅),wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₃, or —C(O)N(R₉)(R₁₀), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, wherein R₈ is—H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, wherein R₈is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,wherein R₈ is —H, —CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀,—N(R₉)C(O)N(R₉)(R₁₀), —N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀),—OR₁₀, —N(R₉)C(O)R₁₃, or —C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W isC(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, wherein R₈ is —H,—CN, oxo, —N(R₉)C(O)R₁₀, —N(R₉)C(O)OR₁₀, —N(R₉)C(O)N(R₉)(R₁₀),—N(R₉)S(O)₂R₁₀, —S(O)₂R₁₀, C(O)R₉—N(R₉)(R₁₀), —OR₁₀, —N(R₉)C(O)R₃, or—C(O)N(R₉)(R₁₀), X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₈is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂)(R₂₃),—(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂)(R₂₃),—(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃),—(CH₂)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₅is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃),—(CH₂)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃),—(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃),—(CH₂)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —S₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —S₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₈is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂)(R₂₃),—(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or—N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is H, halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is H,halogen, oxo, —OH, —NH₂, —NO₂, —C(O)N(R₂₁)(R₂₃), —(CH₂)_(o)—C(O)R₂₃,—OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₅is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, andR₁₅ is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is C(R₅), W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, X₁ is C(R₅), R₅is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with one or more R₈,R₈ is C₁₋₆ alkyl, heterocyclyl, aryl, or heteroaryl, wherein the alkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅is C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl,heteroaryl, or aryl is optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with one or more R₈, R₈ is C₁₋₆ alkyl,heterocyclyl, aryl, or heteroaryl, wherein the alkyl, heterocyclyl,aryl, or heteroaryl is optionally substituted with one or more R₁₅, X₁is C(R₅), X₂ is N, W is C(R₆), R₁ is —N(R₂)C(O)R₃, and R₁₅ is C₁₋₆alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl,wherein the alkyl, alkoxy, cycloalkyl, heterocyclyl, heteroaryl, or arylis optionally substituted with one or more R₂₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with two or more R₈, wherein twoR₈ groups, together with the atoms to which they are attached, form aC₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, is optionallysubstituted with one or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆),and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with two or more R₈,wherein two R₈ groups, together with the atoms to which they areattached, form a C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl,spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, isoptionally substituted with one or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), Wis C(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with two or more R₈, wherein twoR₈ groups, together with the atoms to which they are attached, form aC₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, is optionallysubstituted with one or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆),and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with two or more R₈,wherein two R₈ groups, together with the atoms to which they areattached, form a C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl,spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, isoptionally substituted with one or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), Wis C(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is C(R₅), W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with two or more R₈, wherein twoR₈ groups, together with the atoms to which they are attached, form aC₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, is optionallysubstituted with one or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), andR₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with two or more R₈,wherein two R₈ groups, together with the atoms to which they areattached, form a C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl,spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, isoptionally substituted with one or more R₁₅, X₁ is C(R₅), X₂ is N, W isC(R₆), and R₁ is —N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—N(R₂)C(O)R₃.

In one embodiment of the compounds of Formula I, A is C₃₋₈ cycloalkyl, Bis heteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₄₋₈ cycloalkenyl,B is heteroaryl optionally substituted with two or more R₈, wherein twoR₈ groups, together with the atoms to which they are attached, form aC₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl,heterocyclyl, aryl, or heteroaryl, wherein the cycloalkyl,spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, is optionallysubstituted with one or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), andR₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is 6-memberedheteroaryl, B is heteroaryl optionally substituted with two or more R₈,wherein two R₈ groups, together with the atoms to which they areattached, form a C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl,spiroheterocycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein thecycloalkyl, spirocycloalkyl, spiroheterocycloalkyl, or heterocyclyl, isoptionally substituted with one or more R₁₅, X₁ is C(R₅), X₂ is N, W isC(R₆), and R₁ is —C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is C₂₋₆ alkynyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is aryl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

In one embodiment of the compounds of Formula I, A is heterocyclyl, B isheteroaryl optionally substituted with two or more R₈, wherein two R₈groups, together with the atoms to which they are attached, form a C₃₋₆cycloalkyl, C₅₋₆ spirocycloalkyl, spiroheterocycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the cycloalkyl, spirocycloalkyl,spiroheterocycloalkyl, or heterocyclyl, is optionally substituted withone or more R₁₅, X₁ is C(R₅), X₂ is N, W is C(R₆), and R₁ is—C(O)N(R₂)(R₃).

Non-limiting illustrative compounds of the present disclosure include:

-   N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   4-(6-((5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   1-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(N-methylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-(1-cyanocyclopropyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(5-((5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide    azetidin-1-yl(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)methanone,-   4-(6-((5-(N-cyclopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((5-(2-oxo-3-(thiazol-4-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((5-(2-oxo-3-((tetrahydrofuran-2-yl)methyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(N-methyl-2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(N-methylpropan-2-ylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(N-methylcyclopropanesulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-acetamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   2-fluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   3-fluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   (S)-4-(6-((5-(4-isopropyl-2,5-dioxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   2,5-difluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N-(furan-2-ylmethyl)-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(3-oxomorpholino)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-(2-(dimethylamino)-2-oxoethyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((2-methoxypyrimidin-5-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(4-methyl-6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   4-(6-((5-(N-isopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(1-carbamoylcyclopropyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-methoxypyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-ethyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N-(pyridin-3-yl)pyridin-2-amine,-   N,N-dimethyl-4-(6-(pyrimidin-5-ylamino)pyridin-3-yl)benzamide,-   4-(6-((5-cyanopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-benzyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzenesulfonamide,-   N,N,2-trimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   (4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone,-   N,N-dimethyl-4-(6-((2-methylpyrimidin-5-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-6′-(pyridin-3-ylamino)-[3,3′-bipyridine]-6-carboxamide,-   4-(6-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((2-methylpyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-6′-(pyridin-3-ylamino)-[2,3′-bipyridine]-5-carboxamide,-   5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-N,N-dimethylnicotinamide,-   N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohex-3-ene-1-carboxamide,-   N,N-dimethyl-4-(6-(pyrazin-2-ylamino)pyridin-3-yl)benzamide,-   N-methyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   (1r,4r)-N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohexane-1-carboxamide,-   N,N,3-trimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide,-   N-methyl-N-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)acetamide,-   N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)-N-(pyridin-3-ylmethyl)benzamide,-   N,N-dimethyl-5-(6-(pyridin-3-ylamino)pyridin-3-yl)thiophene-2-carboxamide,-   4-(6-acetamidopyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-3-(6-(pyridin-3-ylamino)pyridin-3-yl)propiolamide,-   (1s,4s)-N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohexane-1-carboxamide,-   N,N-dimethyl-4-(6-((2-oxo-1,2-dihydropyridin-4-yl)amino)pyridin-3-yl)benzamide,-   2-fluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide,-   3-fluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide,-   N,N-dimethyl-4-(5-(pyridin-3-ylamino)pyrazin-2-yl)benzamide,-   2,5-difluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide,-   N,N-dimethyl-4-(6-((6-morpholinopyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((1-acetyl-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   tert-butyl    7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate,-   N,N-dimethyl-4-(6-((5-(1-oxoisoindolin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   (R)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   (S)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(4-ethyl-6-(pyridin-3-ylamino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((1-benzoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   tert-butyl    (3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate,-   4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   tert-butyl    (3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate,-   N,N-dimethyl-4-(6-((1-picolinoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide,-   tert-butyl    (3-(((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamate,-   (E)-4-(6-((6-((3-(4-(dimethylamino)but-2-enamido)benzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   methyl    7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate,-   N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)-N-(thiazol-5-ylmethyl)benzamide,-   1-(4-(6-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (R)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   4-(6-((3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((6-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(difluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   1-(4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N,N-dimethyl-4-(6-((5-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((1-(2-hydroxyacetyl)-2,3-dihydro-TH-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((1-(2-hydroxypropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-TH-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-yl    acetate,-   4-(6-((1-(3-hydroxy-2,2-dimethylpropanoyl)-2,3-dihydro-TH-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(4-aminobenzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(3-aminobenzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(3-(3-(3-aminophenyl)propanamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(3-(3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(3-(2-aminoacetamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-N,N-dimethyl-4-(6-((5-(3-(2-methyl-6-oxo-10,13-dioxa-2,7-diazahexadec-4-en-16-amido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   (E)-4-(6-((5-(3-(3-(2-(4-(dimethylamino)but-2-enamido)acetamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((2-methyloxazolo[4,5-b]pyridin-6-yl)amino)pyridin-3-yl)benzamide,-   4-(6-([1,3]dioxolo[4,5-b]pyridin-6-ylamino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(4-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(4-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(4-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(4-(2-aminoacetamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(4-(2-(4-(dimethylamino)but-2-enamido)acetamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide,-   4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(4-(3-(3-aminophenyl)propanamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-4-(6-((5-(3-(4-(3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)benzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(4-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-benzamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(2-cyanoacetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((5-(2-phenylacetamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)picolinamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-6-carboxamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzo[d]oxazole-6-carboxamide,-   N,N-dimethyl-4-(6-((5-(3-phenylpropanamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N,N-dimethyl-4-(6-((5-(2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   4-(6-((5-(3-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   4-(6-((5-(4-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-4-carboxamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-4-carboxamide,-   methyl    (5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamate,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)nicotinamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-benzo[d]imidazole-7-carboxamide,-   (E)-4-(6-((5-(3-(3-(6-(4-(dimethylamino)but-2-enamido)hexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N,N-dimethyl-4-(6-((5-(3-methylureido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   2-amino-N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide,-   (E)-4-(6-((5-(3-(3-(2-(4-(dimethylamino)but-2-enamido)acetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   (E)-1-(4-(dimethylamino)but-2-enoyl)-N-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide,-   N,N-dimethyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide,-   1-(4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N-methyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide,-   N-methyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide,-   1-(4-(6-((5-(pyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one-   1-(4-(6-((5-(3-hydroxypyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N,N-dimethyl-2-(6-(pyridin-3-ylamino)pyridin-3-yl)pyrimidine-5-carboxamide,-   1-(4-(6-((1-(1-hydroxycyclopropane-1-carbonyl)-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N,N-dimethyl-4-(6-((5-(methylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamide,-   4-(6-((5-(3-(3-aminobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   1-(4-(6-((1-isobutyryl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)acetamide,-   N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylmethanesulfonamide,-   1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one,-   1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one,-   methyl    7-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate,-   1-(4-(6-((1-(cyclopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide,-   N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylacetamide,-   1-(4-(6-((1-(2-hydroxypropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(4-(6-((1-(2-hydroxyacetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(oxazol-4-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one,-   (S)-2-((5-(4-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   1-(4-(6-((1-(2-hydroxy-2-methylpropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(oxazol-5-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one,-   (S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   5-methoxy-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)nicotinamide,-   6-oxo-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1,6-dihydropyridine-3-carboxamide,-   1-(4-(6-((5-(4-(3-methoxypropanoyl)piperazin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   1-(4-(6-((1-(isopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (S)—N,N-dimethyl-4-(6-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)benzamide,-   2,3-difluoro-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide,-   (R)-1-(4-(6-((5-(4-(tetrahydrofuran-3-carbonyl)piperazin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (S)-1-(4-(6-((5-(4-(tetrahydrofuran-3-carbonyl)piperazin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-2-phenylcyclopropane-1-carboxamide,-   1-ethyl-6-oxo-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1,6-dihydropyridine-3-carboxamide,-   6-ethoxy-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)nicotinamide,-   1-(5-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one,-   2-methyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)morpholine-4-carboxamide,-   N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)morpholine-4-carboxamide,-   (1S,2S)-2-ethoxy-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)cyclopropane-1-carboxamide,-   5-methoxy-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-benzo[d]imidazole-7-carboxamide,-   N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-2H-tetrazole-5-carboxamide,-   (S)-8,8-dimethyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   3-methyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxamide,-   3-cyclopropyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxamide,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8,8-dimethyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (E)-4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)but-2-enamide,-   4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)butanamide,-   4-(4-(dimethylamino)butanamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide,-   (6aS)-8-methyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (6aS)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-methyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (E)-4-(4-(dimethylamino)but-2-enamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide,-   2-cyclopropyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)morpholine-4-carboxamide,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methoxypyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4′-(difluoromethyl)-5-(2-oxopyrrolidin-1-yl)-[2,3′-bipyridin]-6′-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (E)-4-(dimethylamino)-N-(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide,-   (S)-2-((5-(3,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(2,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((6-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridazin-3-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((6-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   N,N-dimethyl-4-(2-(pyridin-3-ylamino)pyrimidin-5-yl)benzamide,-   (S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (R)-8-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-3a,4-dihydro-1H,3H-oxazolo[3,4-d]pyrido[2,3-b][1,4]oxazin-1-one,-   (S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((4-(2-aminopropan-2-yl)-5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2′-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((3-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-cyclopropyl-5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   1-(4-(6-((5-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (E)-4-(dimethylamino)-N-(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide,-   (6aS)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-hydroxy-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (6aS)-8-hydroxy-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (6aR)-2-((5-(4-(1-methyl-2-oxopyrrolidin-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (6aS,8R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-hydroxy-8-methyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (6aS,8R)-8-hydroxy-8-methyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   N-methyl-4-[6-[[5-(2-oxopyrrolidin-1-yl)-3-pyridyl]amino]-3-pyridyl]benzamide,-   N,N-dimethyl-4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide,-   4′-((5-(2-(dimethylamino)-2-oxoethyl)pyridin-3-yl)amino)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide,-   1-(4-(6-((6-methoxypyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   4-(6-((6-((3-aminobenzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide,-   N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide,-   3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide,-   (S)-1-(4-(6-((2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one,-   (S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (3S,6R)—N,N-dimethyl-6-(6-(((S)-9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxamide,-   (S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,-   (S)-2-((4-(3-methoxycyclobutyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((1′-(4-methyl-4H-1,2,4-triazol-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-6-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(4-methylpyridazin-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(4-methylisoxazol-5-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-isopropyl-5-(4-(5-methyl-1H-1,2,3-triazol-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(3-methyl-2-oxo-1-oxa-3,8-diazaspiro[4.5]decan-8-yl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-morpholino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-(4-methylpiperazin-1-yl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-(methoxymethyl)-5-(4-(4-methylisoxazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(4-methylisoxazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-cyclobutoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-cyclopropyl-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-(3-methoxyazetidin-1-yl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methoxy-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methoxy-5-(4-(5-methyl-TH-1,2,3-triazol-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(5-methyl-TH-1,2,3-triazol-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((4-methoxy-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   4-(4-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)oxy)acetamido)butanamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide,-   (S)-4-(4-(methoxymethyl)-2-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyrimidin-5-yl)-N,N-dimethylbenzamide,-   (S)-4-(4-methoxy-2-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyrimidin-5-yl)-N,N-dimethylbenzamide,-   (R)-8-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-3a,4-dihydro-1H,3H-oxazolo[3,4-d]pyrido[2,3-b][1,4]oxazin-1-one,-   4-(2-(2-(2-(2-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindolin-4-yl)amino)ethoxy)ethoxy)ethoxy)acetamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide,-   (S)-2-((5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)—N,N-dimethyl-4-(2-((9′-oxo-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-2′-yl)amino)pyrimidin-5-yl)benzamide,-   (S)-2-fluoro-N,N-dimethyl-4-(2-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyrimidin-5-yl)benzamide,-   (S)-2-((5-(4-((R)-2-methyl-5-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(pyrrolidine-1-carbonyl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)-2-((5-(4-(azetidine-1-carbonyl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,-   (S)—N,N-dimethyl-4-(2-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyrimidin-5-yl)benzamide,-   (S)-2-((9-fluoro-5,5-dimethyl-8-(2-oxopyrrolidin-1-yl)-5H-chromeno[3,4-d]pyrimidin-3-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,    and-   (S)-2-((5-(4-(2-oxopyrrolidin-1-yl-4,4,5,5-d4)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one.

It should be understood that all isomeric forms are included within thepresent invention, including mixtures thereof. If the compound containsa double bond, the substituent may be in the E or Z configuration. Ifthe compound contains a di-substituted cycloalkyl, the cycloalkylsubstituent may have a cis- or trans configuration. All tautomeric formsare also intended to be included.

Compounds of the invention, and pharmaceutically acceptable salts,hydrates, solvates, stereoisomers and prodrugs thereof may exist intheir tautomeric form (for example, as an amide or imino ether). Allsuch tautomeric forms are contemplated herein as part of the presentinvention.

The compounds of the invention may contain asymmetric or chiral centers,and, therefore, exist in different stereoisomeric forms. It is intendedthat all stereoisomeric forms of the compounds of the invention as wellas mixtures thereof, including racemic mixtures, form part of thepresent invention. In addition, the present invention embraces allgeometric and positional isomers. For example, if a compound of theinvention incorporates a double bond or a fused ring, both the cis- andtrans-forms, as well as mixtures, are embraced within the scope of theinvention. Each compound herein disclosed includes all the enantiomersthat conform to the general structure of the compound. The compounds maybe in a racemic or enantiomerically pure form, or any other form interms of stereochemistry. The assay results may reflect the datacollected for the racemic form, the enantiomerically pure form, or anyother form in terms of stereochemistry.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or Mosher's acid chloride),separating the diastereomers and converting (e.g., hydrolyzing) theindividual diastereomers to the corresponding pure enantiomers. Also,some of the compounds of the invention may be atropisomers (e.g.,substituted biaryls) and are considered as part of this invention.Enantiomers can also be separated by use of a chiral HPLC column.

It is also possible that the compounds of the invention may exist indifferent tautomeric forms, and all such forms are embraced within thescope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, esters and prodrugs of the compounds as well as the salts,solvates and esters of the prodrugs), such as those which may exist dueto asymmetric carbons on various substituents, including enantiomericforms (which may exist even in the absence of asymmetric carbons),rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention, as are positionalisomers (such as, for example, 4-pyridyl and 3-pyridyl). (For example,if a compound of Formula (I) incorporates a double bond or a fused ring,both the cis- and trans-forms, as well as mixtures, are embraced withinthe scope of the invention. Also, for example, all keto-enol andimine-enamine forms of the compounds are included in the invention.)Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester,” “prodrug” and the like, isintended to equally apply to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, positional isomers,racemates or prodrugs of the inventive compounds.

The compounds of Formula I may form salts which are also within thescope of this invention. Reference to a compound of the Formula hereinis understood to include reference to salts thereof, unless otherwiseindicated.

The present invention relates to compounds which are modulators ofPI5P4K. In one embodiment, the compounds of the present invention areinhibitors of PI5P4K.

The invention is directed to compounds as described herein andpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof, and pharmaceutical compositionscomprising one or more compounds as described herein, orpharmaceutically acceptable salts, hydrates, solvates, prodrugs,stereoisomers, or tautomers thereof.

Method of Synthesizing the Compounds

The compounds of the present invention may be made by a variety ofmethods, including standard chemistry. Suitable synthetic routes aredepicted in the Schemes given below.

The compounds of Formula (I) may be prepared by methods known in the artof organic synthesis as set forth in part by the following syntheticschemes. In the schemes described below, it is well understood thatprotecting groups for sensitive or reactive groups are employed wherenecessary in accordance with general principles or chemistry. Protectinggroups are manipulated according to standard methods of organicsynthesis (T. W. Greene and P. G. M. Wuts, “Protective Groups in OrganicSynthesis”, Third edition, Wiley, New York 1999). These groups areremoved at a convenient stage of the compound synthesis using methodsthat are readily apparent to those skilled in the art. The selectionprocesses, as well as the reaction conditions and order will be readilyapparent to those skilled in the art and they will recognize if astereocenter exists in the compounds of Formula (I). Accordingly, thepresent invention includes both possible stereoisomers (unless specifiedin the synthesis) and includes not only racemic compounds but theindividual enantiomers and/or diastereomers as well. When a compound isdesired as a single enantiomer or diastereomer, it may be obtained bystereospecific synthesis or by resolution of the final product or anyconvenient intermediate. Resolution of the final product, anintermediate, or a starting material may be affected by any suitablemethod known in the art. See, for example, “Stereochemistry of OrganicCompounds” by E. L. Eliel, S. H. Wilen, and L. N. Mander(Wiley-Interscience, 1994).

The compounds described herein may be made from commercially availablestarting materials or synthesized using known organic, inorganic, and/orenzymatic processes.

Preparation of Compounds

The compounds of the present invention can be prepared in a number ofways well known to those skilled in the art of organic synthesis. By wayof example, compounds of the present invention can be synthesized usingthe methods described below, together with synthetic methods known inthe art of synthetic organic chemistry, or variations thereon asappreciated by those skilled in the art. Preferred methods include butare not limited to those methods described below. Compounds of thepresent invention can be synthesized by following the steps outlined inGeneral Scheme 1 which comprise different sequences of assemblingintermediates or compounds (II). Starting materials are eithercommercially available or made by known procedures in the reportedliterature or as illustrated below.

A compound of formula (I) may be obtained (Scheme 1) by starting from,for example, a compound of formula (II), wherein LG represents a leavinggroup including, but not limited to, halogen (e.g., chlorine, bromine oriodine), or an alkyl-sulfonate, aryl-sulfonate or haloalkyl-sulfonate(e.g., triflate), and reacting said compound (II) with a compound offormula B—NH₂, wherein B—NH₂ is defined below and represents a cyclicamine either as free base or a salt (e.g., HCl, TFA or acetic acid),optionally under the influence of a transition metal catalyst asdescribed in for example Metal-Catalyzed Cross-Coupling Reactions,2^(nd) , Completely Revised and Enlarged Edition by A. de Meijere and F.Diederich, Wiley VCH, 2004.

The reaction may be carried out by coupling of a compound of formula(II), with an appropriate amine of formula B—NH₂. The reaction may alsobe carried out using a suitable metal catalyst including, but notlimited to, a palladium catalyst, for example,(di-tert-butylphosphino)ferrocene palladium (II) dichloride,tetrakis(triphenylphosphine)palladium (0), palladium (II)(diphenylphosphino)ferrocene dichloride, palladium(II) acetate orbis(dibenzylideneacetone) palladium (0). Optionally a suitable ligand,for example, triphenylphosphine, tri-tert-butylphosphine or2-(dicyclohexylphosphino)biphenyl or2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl is employed.Suitable bases, including an alkyl amine base, (e.g., triethyl amine),an alkali metal or alkaline earth metal carbonate or hydroxide, orphosphate base, (e.g., potassium carbonate, sodium carbonate, cesiumcarbonate, sodium hydroxide, or potassium phosphate), may be used in thereaction. Said reaction may be performed at a temperature range between+20° C. and +160° C., in suitable solvents, including, withoutlimitation, toluene, tetrahydrofuran, 2-methyl-tetrahydrofuran,1,4-dioxane, 1,2-dimethoxyethane, acetonitrile, water, ethanol,N,N-dimethylacetamide or N,N-dimethylformamide, or mixtures thereof. Ifenantiomerically pure or enriched compound (II) is used in thisreaction, an enantiomerically pure or enantiomerically enriched compound(I) is obtained.

Compounds of formula (II) and B—NH₂ may be commercially availablecompounds, or known in the literature, or they are prepared by standardprocesses known in the art. A compound of formula (I), (II) or B—NH₂ maybe separated into its enantiomers by standard processes known in the artby for example chromatography on a chiral stationary phase.

Methods of Using the Disclosed Compounds

Another aspect of the invention relates to a method of treating adisease or disorder associated with modulation of PI5P4K. The methodcomprises administering to a patient in need of a treatment for diseasesor disorders associated with modulation of PI5P4K an effective amountthe compositions and compounds of Formula (I).

In another aspect, the present invention is directed to a method ofinhibiting PI5P4K. The method involves administering to a patient inneed thereof an effective amount of a compound of Formula (I).

Another aspect of the present invention relates to a method of treating,preventing, inhibiting or eliminating a disease or disorder in a patientassociated with the inhibition of PI5P4K, the method comprisingadministering to a patient in need thereof an effective amount of acompound of Formula (I). In one embodiment, the disease may be, but notlimited to, cancer or cell proliferative disorder, a metabolic disorder,neurodegenerative disease, and an inflammatory disease.

The present invention also relates to the use of an inhibitor of PI5P4Kfor the preparation of a medicament used in the treatment, prevention,inhibition or elimination of a disease or condition mediated by PI5P4K,wherein the medicament comprises a compound of Formula (I).

In another aspect, the present invention relates to a method for themanufacture of a medicament for treating, preventing, inhibiting, oreliminating a disease or condition mediated by PI5P4K, wherein themedicament comprises a compound of Formula (I).

Another aspect of the present invention relates to a compound of Formula(I) for use in the manufacture of a medicament for treating a diseaseassociated with inhibiting PI5P4K.

In another aspect, the present invention relates to the use of acompound of Formula (I) in the treatment of a disease associated withinhibiting PI5P4K.

Another aspect of the invention relates to a method of treating cancer.The method comprises administering to a patient in need thereof aneffective amount of a compound of Formula (I).

In another aspect of the invention, the method relates to treating acell proliferative disease. The method comprises administering to apatient in need thereof an effective amount of a compound of Formula(I).

In yet another aspect, the present invention relates to a method oftreating a neurodegenerative disease. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

In another aspect, the present invention relates to a method of treatingan inflammatory disease or condition. The method comprises administeringto a patient in need thereof an effective amount of a compound ofFormula (I).

Another aspect of the invention relates to a method of inducing cellcycle arrest, apoptosis in tumor cells, and/or enhanced tumor-specific Tcell immunity. The method comprises contacting the cells with aneffective amount of a compound of Formula (I).

In one embodiment, the present invention relates to the use of aninhibitor of PI5P4K for the preparation of a medicament used intreatment, prevention, inhibition or elimination of a disease ordisorder associated with cancer or cell proliferative disorder, ametabolic disorder, neurodegenerative disease, and an inflammatorydisease.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of cancers or cell proliferative disorders including, but notlimited to, leukemias (e.g., acute leukemia, acute lymphocytic leukemia,acute myelocytic leukemia, acute myeloblastic leukemia, acutepromyelocytic leukemia, acute myelomonocytic leukemia, acute monocyticleukemia, acute erythroleukemia, chronic leukemia, chronic myelocyticleukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma(Hodgkin's disease, non-Hodgkin's disease), Waldenstrom'smacroglobulinemia, heavy chain disease, and solid tumors such assarcomas and carcinomas (e.g., fibrosarcoma, myxosarcoma, liposarcoma,chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma,endotheliosarcoma, lymphangiosarcoma, lymphangioendothelio sarcoma,synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma,rhabdomyosarcoma, colon carcinoma, pancreatic cancer, breast cancer,ovarian cancer, prostate cancer, squamous cell carcinoma, basal cellcarcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous glandcarcinoma, papillary carcinoma, papillary adenocarcinomas,cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renalcell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma,seminoma, embryonal carcinoma, Wilms tumor, cervical cancer, uterinecancer, testicular cancer, lung carcinoma, small cell lung carcinoma,bladder carcinoma, epithelial carcinoma, glioma, astrocytoma,medulloblastoma, craniopharyngioma, ependymoma, pinealoma,hemangioblastoma, acoustic neuroma, oligodenroglioma, schwannoma,meningioma, melanoma, neuroblastoma, and retinoblastoma).

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of neurodegenerative diseases including, but not limited to,brain trauma, spinal cord trauma, trauma to the peripheral nervoussystem, Alzheimer's disease, Pick's disease, diffuse Lewy body disease,progressive supranuclear palsy (Steel-Richardson syndrome), multisystemdegeneration (Shy-Drager syndrome), motor neuron diseases includingamyotrophic lateral sclerosis, degenerative ataxias, cortical basaldegeneration, ALS-Parkinson's-Dementia complex of Guam, subacutesclerosing panencephalitis, Huntington's disease, Parkinson's disease,synucleinopathies, primary progressive aphasia, striatonigraldegeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 andolivopontocerebellar degenerations, Gilles De La Tourette's disease,bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy(Kennedy's disease), primary lateral sclerosis, familial spasticparaplegia, Werdnig-Hoffman disease, Kugelberg-Welander disease,Tay-Sach's disease, Sandhoff disease, familial spastic disease,Wohlfart-Kugelberg-Welander disease, spastic paraparesis, progressivemultifocal leukoencephalopathy, and prion diseases (includingCreutzfeldt-Jakob, Gerstmann-Straussler-Scheinker disease, Kuru andfatal familial insomnia, age-related dementia, vascular dementia,diffuse white matter disease (Binswanger's disease), dementia ofendocrine or metabolic origin, dementia of head trauma and diffuse braindamage, dementia pugilistica or frontal lobe dementia, neurodegenerativedisorders resulting from cerebral ischemia or infarction includingembolic occlusion and thrombotic occlusion as well as intracranialhemorrhage of any type, intracranial and intravertebral lesions,hereditary cerebral angiopathy, normeuropathic hereditary amyloid,Down's syndrome, macroglobulinemia, secondary familial Mediterraneanfever, Muckle-Wells syndrome, multiple myeloma, pancreatic- andcardiac-related amyloidosis, chronic hemodialysis arthropathy, andFinnish and Iowa amyloidosis.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory disease. In some embodiments, the inflammatorydisease is associated with a metabolic disorder. In some embodiments thetreated inflammation is associated with, but not limited to, Type IIdiabetes, insulin resistance cardiovascular disease, arrhythmia,atherosclerosis, coronary artery disease, hypertriglyceridemia,dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, and macularedema.

In yet another embodiment, the present invention relates to a compoundof Formula (I) or a pharmaceutical composition comprising a compound ofthe present invention and a pharmaceutically acceptable carrier used forthe treatment of a metabolic disease including, but not limited, Type IIdiabetes, insulin resistance cardiovascular disease, arrhythmia,atherosclerosis, coronary artery disease, hypertriglyceridemia,dyslipidemia, retinopathy, nephropathy, neuropathy, obesity, and macularedema.

In another embodiment, the present invention relates to a compound ofFormula (I) or a pharmaceutical composition comprising a compound of thepresent invention and a pharmaceutically acceptable carrier used for thetreatment of inflammatory disease associated with inflammatory disease.In some embodiments the treated inflammation is associated with, but notlimited to, ileitis, ulcerative colitis, Barrett's syndrome, or Crohn'sdisease.

In some embodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of PI5P4K. In otherembodiments, the patient is selected for treatment based on geneamplification and/or elevated tumor expression of PI5P4Kα gene, PI5P4Kβgene, or PI5P4Kγ gene. In other embodiments, the patient is selected forthe treatment based on tumor expression of p53 mutations.

In some embodiments, administration of a compound of Formula (I) or apharmaceutical composition comprising a compound of the presentinvention and a pharmaceutically acceptable carrier induces a change inthe cell cycle or cell viability.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

In one embodiment, are provided methods of treating a disease ordisorder associated with modulation of PI5P4K including, cancer or cellproliferative disorder, a metabolic disorder, neurodegenerative disease,and an inflammatory disease, comprising administering to a patientsuffering from at least one of said diseases or disorder a compound ofFormula (I).

One therapeutic use of the compounds or compositions of the presentinvention which inhibit PI5P4K is to provide treatment to patients orsubjects suffering from c cancer or cell proliferative disorder, ametabolic disorder, neurodegenerative disease, and an inflammatorydisease.

The disclosed compounds of the invention can be administered ineffective amounts to treat or prevent a disorder and/or prevent thedevelopment thereof in subjects.

Administration of the disclosed compounds can be accomplished via anymode of administration for therapeutic agents. These modes includesystemic or local administration such as oral, nasal, parenteral,transdermal, subcutaneous, vaginal, buccal, rectal or topicaladministration modes.

Depending on the intended mode of administration, the disclosedcompositions can be in solid, semi-solid or liquid dosage form, such as,for example, injectables, tablets, suppositories, pills, time-releasecapsules, elixirs, tinctures, emulsions, syrups, powders, liquids,suspensions, or the like, sometimes in unit dosages and consistent withconventional pharmaceutical practices. Likewise, they can also beadministered in intravenous (both bolus and infusion), intraperitoneal,subcutaneous or intramuscular form, and all using forms well known tothose skilled in the pharmaceutical arts.

Illustrative pharmaceutical compositions are tablets and gelatincapsules comprising a Compound of the Invention and a pharmaceuticallyacceptable carrier, such as a) a diluent, e.g., purified water,triglyceride oils, such as hydrogenated or partially hydrogenatedvegetable oil, or mixtures thereof, corn oil, olive oil, sunflower oil,safflower oil, fish oils, such as EPA or DHA, or their esters ortriglycerides or mixtures thereof, omega-3 fatty acids or derivativesthereof, lactose, dextrose, sucrose, mannitol, sorbitol, cellulose,sodium, saccharin, glucose and/or glycine; b) a lubricant, e.g., silica,talcum, stearic acid, its magnesium or calcium salt, sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and/or polyethylene glycol; for tablets also; c) abinder, e.g., magnesium aluminum silicate, starch paste, gelatin,tragacanth, methylcellulose, sodium carboxymethylcellulose, magnesiumcarbonate, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, waxes and/or polyvinylpyrrolidone, if desired; d) adisintegrant, e.g., starches, agar, methyl cellulose, bentonite, xanthangum, algic acid or its sodium salt, or effervescent mixtures; e)absorbent, colorant, flavorant and sweetener; f) an emulsifier ordispersing agent, such as Tween 80, Labrasol, HPMC, DOSS, caproyl 909,labrafac, labrafil, peceol, transcutol, capmul MCM, capmul PG-12, captex355, gelucire, vitamin E TGPS or other acceptable emulsifier; and/or g)an agent that enhances absorption of the compound such as cyclodextrin,hydroxypropyl-cyclodextrin, pentaneG400, pentaneG200.

Liquid, particularly injectable, compositions can, for example, beprepared by dissolution, dispersion, etc. For example, the disclosedcompound is dissolved in or mixed with a pharmaceutically acceptablesolvent such as, for example, water, saline, aqueous dextrose, glycerol,ethanol, and the like, to thereby form an injectable isotonic solutionor suspension. Proteins such as albumin, chylomicron particles, or serumproteins can be used to solubilize the disclosed compounds.

The disclosed compounds can be also formulated as a suppository that canbe prepared from fatty emulsions or suspensions; using polyalkyleneglycols such as propylene glycol, as the carrier.

The disclosed compounds can also be administered in the form of liposomedelivery systems, such as small unilamellar vesicles, large unilamellarvesicles and multilamellar vesicles. Liposomes can be formed from avariety of phospholipids, containing cholesterol, stearylamine orphosphatidylcholines. In some embodiments, a film of lipid components ishydrated with an aqueous solution of drug to a form lipid layerencapsulating the drug, as described in U.S. Pat. No. 5,262,564 which ishereby incorporated by reference in its entirety.

Disclosed compounds can also be delivered by the use of monoclonalantibodies as individual carriers to which the disclosed compounds arecoupled. The disclosed compounds can also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,poly(hydroxypropyl)methacrylamide-phenol, poly(hydroxyethyl)aspanamidephenol, or poly(ethyleneoxide)-polylysine substituted with palmitoylresidues. Furthermore, the Disclosed compounds can be coupled to a classof biodegradable polymers useful in achieving controlled release of adrug, for example, polylactic acid, polyepsilon caprolactone,polyhydroxy butyric acid, polyorthoesters, polyacetals,polydihydropyrans, polycyanoacrylates and cross-linked or amphipathicblock copolymers of hydrogels. In one embodiment, disclosed compoundsare not covalently bound to a polymer, e.g., a polycarboxylic acidpolymer, or a polyacrylate.

Parental injectable administration is generally used for subcutaneous,intramuscular or intravenous injections and infusions. Injectables canbe prepared in conventional forms, either as liquid solutions orsuspensions or solid forms suitable for dissolving in liquid prior toinjection.

Another aspect of the invention is directed to pharmaceuticalcompositions comprising a compound of Formula (I) and a pharmaceuticallyacceptable carrier. The pharmaceutical acceptable carrier may furtherinclude an excipient, diluent, or surfactant.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentpharmaceutical compositions can contain from about 0.1% to about 99%,from about 5% to about 90%, or from about 1% to about 20% of thedisclosed compound by weight or volume.

The dosage regimen utilizing the disclosed compound is selected inaccordance with a variety of factors including type, species, age,weight, sex and medical condition of the patient; the severity of thecondition to be treated; the route of administration; the renal orhepatic function of the patient; and the particular disclosed compoundemployed. A physician or veterinarian of ordinary skill in the art canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter or arrest the progress of the condition.

Effective dosage amounts of the disclosed compounds, when used for theindicated effects, range from about 0.5 mg to about 5000 mg of thedisclosed compound as needed to treat the condition. Compositions for invivo or in vitro use can contain about 0.5, 5, 20, 50, 75, 100, 150,250, 500, 750, 1000, 1250, 2500, 3500, or 5000 mg of the disclosedcompound, or, in a range of from one amount to another amount in thelist of doses. In one embodiment, the compositions are in the form of atablet that can be scored.

EXAMPLES

The disclosure is further illustrated by the following examples andsynthesis schemes, which are not to be construed as limiting thisdisclosure in scope or spirit to the specific procedures hereindescribed. It is to be understood that the examples are provided toillustrate certain embodiments and that no limitation to the scope ofthe disclosure is intended thereby. It is to be further understood thatresort may be had to various other embodiments, modifications, andequivalents thereof which may suggest themselves to those skilled in theart without departing from the spirit of the present disclosure and/orscope of the appended claims.

Analytical Methods, Materials, and Instrumentation

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. All solvents used were of analytical grade andcommercially available anhydrous solvents were routinely used forreactions. Starting materials were available from commercial sources, orprepared according to literature procedures. Room temperature refers to+20-25° C. Solvent mixture compositions are given as volume percentagesor volume ratios.

Microwave heating was performed in a Biotage Initiator microwave cavityproducing continuous irradiation at 2.45 GHz. It is understood thatmicrowaves may be used for the heating of reaction mixtures.

Straight phase chromatography was manually performed on Merck Silica gel60 (0.040-0.063 mm), or automatically using an ISCO Combiflash®Companion™ system using SiliaSep™ normal-phase flash columns using thesolvent system indicated.

NMR spectra were recorded on a 400 MHz (or higher field) NMRspectrometer fitted with a probe of suitable configuration. Spectra wererecorded at ambient temperature unless otherwise stated. Chemical shiftsare given in ppm down- and upfield from TMS (0.00 ppm). The followingreference signals were used: the residual solvent signal ofDMSO-d_(6 δ 2.5), CDCl3 δ 7.26 or Methanol-d4 δ 3.31. Resonancemultiplicities are denoted s, d, t, q, m and br for singlet, doublet,triplet, quartet, multiplet and broad, respectively.

High pressure liquid chromatography (HPLC) was performed on a reversephase column. A linear gradient was applied using for example mobilephase A (aqueous 0.1% NH₃ or aqueous 0.1% acetic acid or aqueous 0.1%formic acid) and B (acetonitrile or methanol). Mass spectrometer (MS)analyses were performed in positive ion mode using electrosprayionization (ES+).

Preparative chromatography was run on a Gilson-PREP GX271 or GX281 withTrilution 1c as software on a reverse phase column. A linear gradientwas applied using for example mobile phase A (aqueous 0.1% NH₃ oraqueous 0.1% acetic acid or aqueous 0.1% formic acid) and B(acetonitrile or methanol).

Preparative chiral chromatography for separation of enantiomers was runon a Thar SFC using supercritical fluid chromatography on a chiralstationary phase. A linear gradient was applied using mobile phase A(carbon dioxide) and B (acetonitrile or methanol or ethanol or2-propanol or any mixtures thereof). Additives (such as diethyl amine orisopropyl amine or ammonia or formic acid or TFA) may be used.

Abbreviations used in the following examples and elsewhere herein are:

-   -   Ac₂O acetic anhydride    -   AcOH acetic acid    -   ADP adenosine diphosphate    -   Amphos (4-(N,N-dimethylamino)phenyl)di-tert-butyl phosphine    -   anh. anhydrous    -   aq. Aqueous    -   atm atmosphere    -   ATP adenosine triphosphate    -   B₂Pin₂ bis(pinacolato)diboron    -   BH₃.THF borane tetrahydrofuran    -   BINAP (±)-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene    -   Boc tert-butyloxycarbonyl    -   Boc₂O tert-butyloxycarbonyl anhydride    -   Brettphos        2-(dicyclohexylphosphino)3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl    -   Brettphos Pd G3        [(2-di-cyclohexylphosphino-3,6-dimethoxy-2′,4′,6′-triisopropyl-1,1′-biphenyl)-2-(2′-amino-1,1′-biphenyl)]palladium(II)        methanesulfonate    -   br broad    -   brine saturated aqueous sodium chloride    -   n-BuLi n-butyl lithium    -   n-BuOH n-butanol    -   Calc'd calculated    -   CDCl₃ deuterated chloroform    -   CHCl₃ chloroform    -   CoCl₂.6H₂O cobalt chloride hexahydrate    -   Cs₂CO₃ cesium carbonate    -   CuI copper iodide    -   DCM dichloromethane    -   DIAD diisopropyl azodiformate    -   DIPEA N,N-diisopropylethylamine    -   DMAc N,N-dimethyl acetamide    -   DMAP N,N-dimethylpyridin-4-amine    -   DME 1,2-Dimethoxyethane    -   DMEDA N,N′-Dimethylethylenediamine    -   DMF N,N-dimethyl formamide    -   DMFDMA N,N-dimethyl formamide dimethyl acetal    -   2,2-DMP dimethoxypropane    -   DMSO dimethyl sulfoxide    -   DMSO-d₆ deuterated dimethyl sulfoxide    -   DOPE 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine    -   EDA ethylenediamine    -   EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide    -   EDTA ethylenediaminetetraacetic acid    -   EGTA ethylene glycol-bis(β-aminoethyl        ether)-N,N,N′N′-tetraacetic acid    -   ESI electrospray ionization    -   Et₂O diethyl ether    -   EtOAc ethyl acetateEtOH ethanol    -   FA formic acid    -   Fe iron    -   g gram    -   GST glutathione S-transferase    -   h hour(s)    -   H₂ hydrogen gas    -   H₂O₂ hydrogen peroxide    -   HATU        [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxide hexafluorophosphate    -   HBTU 3-[bis(dimethylamino)methylene]-3H-benzotriazol-1-oxide        hexafluorophosphate    -   HBr hydrobromic acid    -   HCl hydrochloric acid    -   HEPES (4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)    -   H₄NE 20 mM HEPES, pH 7.4, 100 mM NaCl, 0.5 mM EGTA    -   HPLC high pressure (or performance) liquid chromatography    -   Hz hertz    -   IPA isopropanol    -   J coupling constant    -   K₂CO₃ potassium carbonate    -   KMnO₄ potassium permanganate    -   KOAc potassium acetate    -   KOtBu potassium tert-butoxide    -   LCMS liquid chromatography mass spectrometry    -   LHMDS lithium bis(trimethylsilyl)amide    -   LiOH lithium hydroxide    -   m multiplet    -   m/z mass-to-charge ratio    -   MBTE methyl tert-butyl ether    -   MeCN acetonitrile    -   MeI methyl iodideMeNH₂ methylamine    -   Me₂NH dimethylamine    -   MeOH methanol    -   Methanol-D₄ deuterated methanol    -   2-MeTHF 2-methyl tetrahydrofuran    -   mg milligram    -   MgCl₂ magnesium chloride    -   MgSO₄ magnesium sulfate    -   MHz megahertz    -   min min    -   mM millimolar    -   mmol millimole    -   mL milliliter    -   MOPS 3-(N-morpholino)propanesulfonic acid    -   MS mass spectrometry    -   MS ES mass spectrometry electrospray    -   MsCl methanesulfonyl chloride    -   Ms₂O methanesulfonic anhydride    -   MTBE methyl tert-butyl ether    -   m/z mass-to-charge ratio    -   μg microgram    -   μM micromolar    -   μL microliter    -   N₂ nitrogen    -   NaBH₄ sodium borohydride    -   NaCl sodium chloride    -   Na₂CO₃ sodium carbonate    -   NaH sodium hydride    -   NaHCO₃ sodium bicarbonate    -   NaOtBu sodium tert-butoxide    -   Na₂SO₄ sodium sulfate    -   NaOH sodium hydroxide    -   NH₃ ammonia    -   NH₄Cl ammonium chloride    -   NH₄HCO₃ ammonium bicarbonate    -   NMR nuclear magnetic resonance    -   Pd/C palladium on carbon    -   PdCl₂(Amphos)        bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II)    -   PdCl₂(PPh₃)₂ bis(triphenylphosphinepalladium(II) dichloride    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium(0)    -   Pd(OAc)₂ palladium(II) acetate    -   PdCl₂(dppf)        [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)    -   Pd(t-Bu₃P)₂ bis(tri-tert-butylphosphine)palladium(0)    -   Pd(PPh₃)₄ tetrakis(triphenylphosphine)palladium(0)    -   PEPPSI-iPr        [1,3-bis(2,6-Diisopropylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)        dichloride    -   pH potential of hydrogen    -   PI5P phosphatidyinositol 5-phosphate    -   PI5P4K phosphatidylinositol-5-phosphate-4-kinase    -   PIP4K2A phsosphatidylinositol 5-phosphate 4-kinase type-2 alpha    -   ppm parts per million    -   psi pounds per square inch    -   py pyridine    -   quant. quantitative    -   R_(f) retention factor    -   rt room temperature    -   Rt retention time    -   sat. saturated    -   SEMCl 2-(trimethylsilyl)ethoxymethyl chloride    -   SOCl₂ thionyl chloride    -   t-BuOH tert-butanol    -   TBAB tetrabutylammonium bromide    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography    -   TMEDA tetramethylethylenediamine    -   Triton X-100 4-(1,1,3,3-tetramethylbutyl)phenyl-polyethylene        glycol    -   Ts₂O tosylic anhydride    -   TsOH tosylic acid    -   Tween 20 PEG(20) sorbitan monolaurate    -   XantPhos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene    -   XPhos 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl    -   XPhos Pd G1        (2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)        chloride, (XPhos) palladium(II) phenethylamine chloride    -   Zn zinc

Example 1: N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

4-Iodo-N,N-dimethyl-benzamide (195 mg, 0.71 mmol),(6-chloro-3-pyridyl)boronic acid (140 mg, 0.89 mmol), Pd(PPh₃)₄ (40 mg,0.03 mmol) and K₂CO₃ (300 mg, 2.17 mmol) were taken up in1,4-Dioxane:H₂O:EtOH (6:3:1, 5 mL). The resulting mixture was stirred at70° C. for 3 h and then allowed to cool to rt overnight. Water (5 mL)was added and the mixture extracted with EtOAc (3×10 mL). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give crude product (248 mg).4-(6-chloro-3-pyridyl)-N,N-dimethyl-benzamide (180 mg, 0.69 mmol, fromprevious step), Pd(OAc)₂ (7.75 mg, 0.03 mmol), BINAP (43 mg, 0.07 mmol),KOtBu (232 mg, 2.07 mmol) and pyridin-3-amine (130 mg, 1.38 mmol) weretaken up in 1,4-Dioxane and the resulting mixture was stirred at 90° C.overnight. When cooled to rt water (5 mL), brine (5 mL) and EtOAc (10mL) were added, the mixture was filtered and the organic layerseparated. The aqueous layer was extracted with EtOAc (2×10 mL). Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by preparative HPLC to give product as a solid(27 mg, 12%). ¹H NMR (500 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.84 (d, J=2.2Hz, 1H), 8.57 (d, J=1.9 Hz, 1H), 8.26 (br d, J=8.2 Hz, 1H), 8.12 (d,J=3.8 Hz, 1H), 7.99 (dd, J=2.4, 8.7 Hz, 1H), 7.72 (d, J=8.2 Hz, 2H),7.48 (d, J=8.2 Hz, 2H), 7.31 (dd, J=4.6, 8.4 Hz, 1H), 6.97 (d, J=8.8 Hz,1H), 3.16-2.80 (m, 6H). MS ES+m/z 319 [M+H]⁺.

Example 2:N,N,3-trimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

The title compound was synthesized in a similar way as described inExample 1, starting from 4-bromo-N,N,3-trimethyl-benzamide, to give theproduct as a solid (5 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.32 (s,3H) 2.94-3.05 (m, 6H) 6.96 (d, 1H) 7.28-7.36 (m, 4H) 7.69 (dd, 1H) 8.12(d, 1H) 8.21 (d, 1H) 8.28 (br d, 1H) 8.85 (d, 1H) 9.44 (s, 1H). MSES+m/z 333 [M+H]⁺.

Example 3:N,N-dimethyl-6′-(pyridin-3-ylamino)-[3,3′-bipyridine]-6-carboxamide

The title compound was synthesized in a similar way as described inExample 1, starting from 5-bromo-N,N-dimethyl-pyridine-2-carboxamide, togive the product as a solid (35 mg, 24%). ¹H NMR (500 MHz, DMSO-d₆) δppm 3.03 (d, 6H) 7.00 (d, 1H) 7.33 (dd, 1H) 7.64 (d, 1H) 8.08 (dd, 1H)8.14 (d, 1H) 8.21 (dd, 1H) 8.27 (br d, 1H) 8.66 (d, 1H) 8.86 (d, 1H)8.89-8.95 (m, 1H) 9.52 (s, 1H). MS ES+m/z 320 [M+H]⁺.

Example 4:N,N-dimethyl-3-(6-(pyridin-3-ylamino)pyridin-3-yl)propiolamide

Step 1: Intermediate 1—3-(6-Chloro-3-pyridyl)prop-2-ynoic acid

2-Chloro-5-iodo-pyridine (500 mg, 2.09 mmol), prop-2-ynoic acid (154 mg,2.19 mmol), PdCl₂(PPh₃)₂ (22 mg, 0.03 mmol) and CuI (16 mg, 0.08 mmol)were taken up in 2-MeTHF (5 mL). TEA (1 mL, 7.19 mmol) was added and theresulting mixture was stirred at rt for 2 h. EtOAc (3 mL), 2M aq. NaOH(3 mL) and water (10 mL) were added and the aqueous layer separated. Theorganic layer was extracted with 0.2M aq NaOH (5 mL). The combinedaqueous layers were washed with EtOAc (5 mL) and filtered. pH wasadjusted to ˜2 using conc. HCl and the mixture was stirred at rt for 10min. The resulting precipitate was filtered off, washed with water anddried to give the product as a solid (210 mg, 55%). MS ES+m/z 182[M+H]⁺.

Step 2: Intermediate—3-(6-Chloro-3-pyridyl)-N,N-dimethyl-prop-2-ynamide

3-(6-Chloro-3-pyridyl)prop-2-ynoic acid (210 mg, 1.16 mmol) was taken upin SOCl₂ (3 mL, 41 mmol) and the resulting mixture was stirred at 80° C.for 1 h. The mixture was concentrated and the resulting residue wastaken up in THF (10 mL) and cooled to 0° C. Dimethylamine HCl salt (472mg, 5.78 mmol) and TEA (1 mL, 7.19 mmol) were added and the mixture wasstirred at 0° C. for 30 min and then at rt for 1 h. The mixture wasconcentrated and the resulting residue was taken up in DCM (10 mL),filtered and purified on a silica gel column eluted with 0-75% EtOAc inHeptane to give the product as a solid (30 mg, 12%). MS ES+m/z 209[M+H]⁺.

Step 3: N,N-dimethyl-3-(6-(pyridin-3-ylamino)pyridin-3-yl)propiolamide

3-(6-Chloro-3-pyridyl)-N,N-dimethyl-prop-2-ynamide (30 mg, 0.14 mmol),pyridin-3-amine (18 mg, 0.19 mmol),(2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2-aminoethyl)phenyl)]palladium(II)chloride (11 mg, 0.01 mmol) and Cs₂CO₃ (94 mg, 0.29 mmol) were taken upin 2-MeTHF (1.5 mL) and the resulting mixture was heated in a microwavereactor at 120° C. for 1 h. Heated again at 130° C. for 1 h. When cooledto rt the mixture was filtered, concentrated and purified by preparativeHPLC to give the product as a solid. ¹H NMR (500 MHz, METHANOL-d4) δ ppm3.24-3.29 (m, 6H), 6.88 (d, J=8.51 Hz, 1H), 7.36 (dd, J=8.35, 4.57 Hz,1H), 7.76 (dd, J=8.83, 2.21 Hz, 1H), 8.12-8.19 (m, 1H), 8.27-8.33 (m,1H), 8.42-8.46 (m, 1H), 8.83 (d, J=2.21 Hz, 1H). MS ES+m/z 267 [M+H]⁺.

Example 5:N,N-dimethyl-5-(6-(pyridin-3-ylamino)pyridin-3-yl)thiophene-2-carboxamide

Step 1: Intermediate 35-(6-Chloro-3-pyridyl)-N,N-dimethyl-thiophene-2-carboxamide

(6-Chloro-3-pyridyl)boronic acid (185 mg, 1.17 mmol),5-bromo-N,N-dimethyl-thiophene-2-carboxamide (183 mg, 0.78 mmol),Pd(PPh₃)₄ (45 mg, 0.04 mmol) and K₂CO₃ (324 mg, 12.35 mmol) were takenup in 1,4-Dioxane:H₂O:EtOH (6:3:1, 3 mL) and the resulting mixture wasstirred at 80° C. overnight. Additional Pd(PPh₃)₄ (45 mg) was added andthe mixture heated in a microwave reactor at 130° C. for 15 min. Whencooled to rt the mixture was concentrated and the resulting residue wastaken up in DCM (20 mL) and water (10 mL). The organic layer wasseparated and the aqueous layer extracted with DCM (2×20 mL). Thecombined organics were washed with water and brine, dried over Na₂SO₄,filtered, concentrated and purified on a silica gel column, eluted with0-100% EtOAc in Heptane, to give the product as a solid (61 mg, 29%). MSES+m/z 267 [M+H]⁺.

Step 2:N,N-dimethyl-5-(6-(pyridin-3-ylamino)pyridin-3-yl)thiophene-2-carboxamide

PEPPSI-iPr (12 mg, 0.02 mmol), Cs₂CO₃ (126 mg, 0.39 mmol)pyridin-3-amine (32 mg, 0.34 mmol) and5-(6-chloro-3-pyridyl)-N,N-dimethyl-thiophene-2-carboxamide (61 mg, 0.23mmol) were dissolved in dry degassed 1,4-Dioxane:DMF (2 mL, 3:1) and themixture was stirred at 80° C. overnight. The reaction mixture wastransferred to a microwave vial and heated in a microwave reactor at130° C. for 80 min. When cooled to rt the mixture was concentrated andthe resulting residue was taken up in EtOAc (20 mL) and water (10 mL).The organic layer was separated and the aqueous layer extracted withEtOAc (2×20 mL). The combined organics were washed with water and brine,dried over Na₂SO₄, filtered, concentrated and purified by preparativeHPLC to give the product as a solid (11 mg, 14%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 3.33 (s, 6H) 6.94 (d, J=8.83 Hz, 1H) 7.32 (dd, J=8.35,4.57 Hz, 1H) 7.44 (d, J=3.78 Hz, 1H) 7.47-7.54 (m, 1H) 7.95 (dd, J=8.67,2.36 Hz, 1H) 8.14 (d, J=4.41 Hz, 1H) 8.17-8.29 (m, 1H) 8.57 (d, J=2.21Hz, 1H) 8.83 (d, J=2.52 Hz, 1H) 9.53 (br s, 1H). MS ES+m/z 325 [M+H]⁺.

Example 6:N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohex-3-ene-1-carboxamide

Step 1: Intermediate 4—Methyl4-(6-chloro-3-pyridyl)cyclohex-3-ene-1-carboxylate

Methyl4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-ene-1-carboxylate(1.1 g, 4.13 mmol), 2-chloro-5-iodo-pyridine (1 g, 4.18 mmol), Pd(PPh₃)₄(250 mg, 0.22 mmol) and K₂CO₃ (1.71 g, 12.4 mmol) were taken up in1,4-Dioxane (15 mL) and water (5 mL). The mixture was degassed withnitrogen for 5 min, then stirred at 70° C. for 5 h. When cooled to rtthe mixture was filtered and the precipitate discarded. The filtrate wasdiluted with water (5 mL) and EtOAc (20 mL). The organic layer wasseparated and the aqueous layer extracted with EtOAc (2×10 mL). Thecombined organics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified on a silica gel column, eluted with 0-50%EtOAc in Heptane, to give the product as a solid (300 mg, 29%). MSES+m/z 252 [M+H]⁺.

Step 2: Intermediate5—4-(6-Chloro-3-pyridyl)-N,N-dimethyl-cyclohex-3-ene-1-carboxamide

Methyl 4-(6-chloro-3-pyridyl)cyclohex-3-ene-1-carboxylate (300 mg, 1.19mmol) was taken up in MeOH (3 mL), THF (5 mL) and water (1 mL). LiOHhydrate (60 mg, 1.43 mmol) was added and the resulting mixture wasstirred at 50° C. overnight. The mixture was concentrated and theresidue was taken up in SOCl₂ (4 mL, 55 mmol), stirred at 80° C. for 2 hand then concentrated. In a separate flask, dimethylamine HCl (486 mg,5.96 mmol) and DIPEA (2 mL, 11.48 mmol) were taken up in THF at 0° C. Asolution of the crude acid chloride in THF (5 mL) was added slowly andthe resulting mixture was stirred at rt for 1 h. Water (10 mL) and EtOAc(10 mL) were added and the organic layer separated. The aqueous layerwas extracted with EtOAc (2×5 mL) and the combined organics were washedwith brine, dried over Na₂SO₄, filtered and concentrated to give theproduct as a solid (310 mg, 98%). MS ES+m/z 265 [M+H]⁺.

Step 3:N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohex-3-ene-1-carboxamide

4-(6-Chloro-3-pyridyl)-N,N-dimethyl-cyclohex-3-ene-1-carboxamide (310mg, 1.17 mmol), pyridin-3-amine (143 mg, 1.52 mmol), TEA (0.08 mL, 0.59mmol), 2-(2′-Di-tert-butylphosphine)biphenyl palladium(II) acetate (27mg, 0.06 mmol) and NaOtBu (169 mg, 1.76 mmol) were taken up in Toluene(5 mL) and the resulting mixture was stirred at 80° C. overnight.PEPPSI-iPr (60 mg, 0.09 mmol) and DMF (2 mL) were added and the mixturewas stirred at 130° C. for 1.5 h. When cooled to rt water (10 mL), EtOAc(10 mL) and brine (2 mL) were added and the organic layer separated. Theaqueous layer was extracted with EtOAc (2×10 mL) and the combinedorganics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by preparative HPLC to give the product as asolid (40 mg, 11%). ¹H NMR (500 MHz, CDCl₃) δ=8.59 (d, J=2.5 Hz, 1H),8.31-8.25 (m, 2H), 7.99 (d, J=8.2 Hz, 1H), 7.59 (d, J=8.3 Hz, 1H),7.30-7.25 (m, 1H, obscured by CDCl₃), 6.79 (d, J=8.8 Hz, 1H), 6.63 (s,1H), 6.11-6.08 (m, 1H), 3.15-3.11 (m, 3H), 3.00 (s, 3H), 2.87-2.81 (m,1H), 2.60-2.42 (m, 3H), 2.36-2.29 (m, 1H), 2.07-2.00 (m, 1H), 1.95-1.80(m, 1H). MS ES+m/z 323 [M+H]⁺.

Example 7:(r,4r)-N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohexane-1-carboxamide

Pd/C (10%, 100 mg, 0.09 mmol) was weighed into a miniclave flask andcovered with EtOAc (2 mL). A solution ofN,N-dimethyl-4-[6-(3-pyridylamino)-3-pyridyl]cyclohex-3-ene-1-carboxamide(30 mg, 0.09 mmol) in MeOH (5 mL) was added carefully and the resultingmixture was stirred at rt under a hydrogen atmosphere (1.5 bar) for 3 h.The mixture was filtered, concentrated and purified by preparative HPLCto give the products as solids.

First isomer to elute (3 mg, 10%);

¹H NMR (500 MHz, CDCl₃) δ=8.57 (d, J=2.5 Hz, 1H), 8.24 (dd, J=1.4, 4.6Hz, 1H), 8.11 (d, J=2.2 Hz, 1H), 7.98-7.93 (m, 1H), 7.41 (dd, J=2.2, 8.5Hz, 1H), 7.25 (br dd, J=4.6, 8.4 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 6.52(s, 1H), 3.09 (s, 3H), 3.00-2.96 (m, 3H), 2.64-2.51 (m, 2H), 2.11-1.95(m, 2H), 1.94-1.84 (m, 2H), 1.74 (dq, J=3.2, 12.8 Hz, 2H), 1.48 (dq,J=3.3, 12.9 Hz, 2H). MS ES+m/z 325 [M+H]⁺.

Example 8:(1s,4s)-N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)cyclohexane-1-carboxamide

Pd/C (10%, 100 mg, 0.09 mmol) was weighed into a miniclave flask andcovered with EtOAc (2 mL). A solution ofN,N-dimethyl-4-[6-(3-pyridylamino)-3-pyridyl]cyclohex-3-ene-1-carboxamide(30 mg, 0.09 mmol) in MeOH (5 mL) was added carefully and the resultingmixture was stirred at rt under a hydrogen atmosphere (1.5 bar) for 3 h.The mixture was filtered, concentrated and purified by preparative HPLCto give the products as solids.

Second isomer to elute (9 mg, 30%);

¹H NMR (500 MHz, CDCl₃) δ=8.55 (d, J=2.5 Hz, 1H), 8.22 (dd, J=1.3, 4.7Hz, 1H), 8.13 (d, J=2.2 Hz, 1H), 7.97 (ddd, J=1.4, 2.6, 8.3 Hz, 1H),7.51 (dd, J=2.2, 8.5 Hz, 1H), 7.26-7.20 (m, J=6.5, 6.5 Hz, 1H), 6.78 (d,J=8.5 Hz, 1H), 6.56 (s, 1H), 3.06 (s, 3H), 2.96 (s, 3H), 2.91-2.86 (m,1H), 2.64-2.56 (m, 1H), 2.14-2.04 (m, 2H), 2.02-1.94 (m, 2H), 1.75-1.68(m, 4H). MS ES+m/z 325 [M+H]⁺.

Example 9:N,N-dimethyl-6′-(pyridin-3-ylamino)-[2,3′-bipyridine]-5-carboxamide

Step 1. Intermediate6—6-(6-Fluoro-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamide

A mixture of 6-chloro-N,N-dimethyl-pyridine-3-carboxamide (383 mg, 2.07mmol), (6-fluoro-3-pyridyl)boronic acid (351 mg, 2.49 mmol),PdCl₂(Amphos) (73 mg, 0.1 mmol) and K₂CO₃ (860 mg, 6.22 mmol) in DME(3.5 mL) and water (1.25 mL) was heated in a microwave reactor at 130°C. for 40 min. EtOAc (20 mL) and brine (20 mL) were added the organiclayer separated. The aqueous layer was extracted with EtOAc (2×40 mL)and the combined organics were washed with brine, dried over Na₂SO₄,concentrated and purified on a silica gel column, eluted with 0-100%EtOAc in Heptane, to give the product as a solid (425 mg, 84%). MSES+m/z 246 [M+H]⁺.

Step 2:N,N-dimethyl-6′-(pyridin-3-ylamino)-[2,3′-bipyridine]-5-carboxamide

To a solution of 3-aminopyridine (138 mg, 1.47 mmol) in 5 mL 2-MeTHF wasadded 1M LHMDS in THF (1.96 mL, 1.96 mmol) at 0° C. under an argonatmosphere. After 15 minutes6-(6-fluoro-3-pyridyl)-N,N-dimethyl-pyridine-3-carboxamide (120 mg, 0.49mmol) in 5 mL 2-MeTHF was added and the mixture was stirred at rt for 1h. Additional 3-aminopyridine (138 mg, 1.47 mmol) and 1M LHMDS (1.96 mL,1.96 mmol), pre-mixed in 2-MeTHF (3 mL), was added and the mixturestirred at rt overnight (repeated twice). Water (40 mL) and EtOAc (20mL) were added, the organic layer separated and the aqueous layer wasextracted with EtOAc (10 mL). The combined organics were washed withbrine, dried over Na₂SO₄, concentrated and purified by preparative HPLCto give the product as a solid (30 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δppm 9.56 (1H, s) 8.96 (1H, d) 8.86 (1H, d) 8.67 (1H, m) 8.35 (1H, dd)8.27 (1H, m) 8.14 (1H, dd) 7.99 (1H, m) 7.90 (1H, dd) 7.33 (1H, dd) 6.98(1H, d) 3.02 (3H, s) 2.99 (3H, br s). MS ES+m/z 320 [M+H]⁺.

Example 10:N,N,2-trimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

Step 1: Intermediate 7—[4-(Dimethylcarbamoyl)-3-methyl-phenyl]boronicacid

4-Carboxy-3-methylphenylboronic acid (500 mg, 2.78 mmol) was dissolvedin DMF (4 mL). DIPEA (2.9 mL, 16.67 mmol) and HATU (1.27 g, 3.33 mmol)were added and the resulting mixture was stirred at rt for 10 min.Dimethylamine HCl (453 mg, 5.56 mmol) was added and the mixture stirredat rt for 3 h. Half-saturated aq. NH₄Cl (50 mL) and EtOAc (50 mL) wereadded, the organic layer was separated and the aqueous layer extractedwith EtOAc (3×50 mL). The combined organic layers were washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the product(954 mg, 83%, 50% purity), which was used in the next step withoutfurther purification. MS ES+m/z 208 [M+H]⁺.

Step 1: Intermediate 8—5-Bromo-N-(3-pyridyl)pyridin-2-amine

1M LHMDS in THF (19.43 mL, 19.43 mmol) was added to a solution ofpyridin-3-amine (1.83 g, 19.43 mmol) in 2-MeTHF (80 mL) at 0° C. under anitrogen atmosphere. After 10 min 5-bromo-2-fluoro-pyridine (1 mL, 9.72mmol) was added and the mixture was stirred at rt for 2.5 h. Water (100mL) and EtOAc (100 mL) were added. The organic layer was separated,washed with brine, dried over Na₂SO₄, filtered, and concentrated. Theresidue was triturated with MeOH and dried to give the product as asolid (968 mg, 40%). MS ES+m/z 250 [M+H]⁺.

Step 3: N,N,2-trimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

A mixture of 5-bromo-N-(3-pyridyl)pyridin-2-amine (150 mg, 0.6 mmol),[4-(Dimethylcarbamoyl)-3-methyl-phenyl]boronic acid (298 mg, 0.72 mmol,50% pure), PdCl₂ (AmPhos) (32 mg, 0.05 mmol) and K₂CO₃ (249 mg, 1.8mmol) in DME (3 mL) and water (1 mL) was heated in a microwave reactorat 130° C. for 40 min. EtOAc (20 mL) and brine (20 mL) were added theorganic layer separated. The aqueous layer was extracted with EtOAc (20mL) and the combined organics were washed with brine, dried over Na₂SO₄,concentrated and purified by preparative HPLC to give the product as asolid (39 mg, 19%). ¹H NMR (500 MHz, METHANOL-d4) δ ppm 2.37 (s, 3H),2.93 (s, 3H), 3.17 (s, 3H), 6.99 (d, J=8.51 Hz, 1H), 7.29 (d, J=7.88 Hz,1H), 7.50-7.59 (m, 3H), 7.96 (dd, J=8.67, 2.36 Hz, 1H), 8.17 (br d,J=4.10 Hz, 1H), 8.35 (m, J=8.30 Hz, 1H), 8.54 (d, J=2.21 Hz, 1H), 9.11(br s, 1H). MS ES+m/z 333 [M+H]⁺.

Example 11:azetidin-1-yl(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)methanone

The title compound was prepared as described in Example 10, startingfrom 5-Bromo-N-(3-pyridyl)pyridin-2-amine and[4-(azetidine-1-carbonyl)phenyl]boronic acid, to give the product as asolid (90 mg, 22%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 8.84 (d,J=2.0 Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 8.25 (d, J=8.4 Hz, 1H), 8.12 (d,J=4.4 Hz, 1H), 8.00 (dd, J=2.4, 8.8 Hz, 1H), 7.75-7.68 (m, 4H),7.32-7.29 (m, 1H), 6.97 (d, J=8.8 Hz, 1H), 4.35-4.33 (m, 2H), 4.07-4.05(m, 2H), 2.31-2.23 (m, 2H). MS ES+m/z 331 [M+H]⁺.

Example 12:2-fluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1 Intermediate9—1-[5-[(5-Bromo-2-pyridyl)amino]-3-pyridyl]pyrrolidin-2-one

A mixture of 1-(5-bromo-3-pyridyl)pyrrolidin-2-one (2 g, 8.29 mmol),5-bromopyridin-2-amine (1.5 g, 9.12 mmol), NaOtBu (1.6 g, 16.5 mmol) andXantphos (0.48 g, 0.82 mmol) in 1,4-Dioxane (40 mL) was degassed withargon for 15 min. Pd₂(dba)₃ (0.75 g, 0.82 mmol) was added and mixturewas stirred at 90° C. for 1 h. When cooled to rt, EtOAc was added andthe mixture filtered through celite. The filtrate was concentrated andpurified on a silica gel column to give the product as a solid (0.9 g,32%). MS ES+m/z 333 [M+H]⁺.

Step 2:2-fluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-Bromo-2-pyridyl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(dimethylcarbamoyl)-3-fluoro-phenyl]boronic acid, to give the productas a solid (19 mg, 10%). ¹H NMR (400 MHz, DMSO-d₆) δ=9.54 (s, 1H), 8.79(s, 1H), 8.62 (s, 1H), 8.57 (s, 1H), 8.38 (s, 1H), 8.02 (dd, J=4.0, 8.8Hz, 2.4 Hz, 1H), 7.65-7.59 (m, 2H), 7.44 (t, 7.6 Hz, 1H), 6.97 (d, J=8Hz, 1H), 3.88 (t, 7 Hz, 2H), 3.02 (s, 3H), 2.89 (s, 3H), 2.54-2.52 (m,2H), 2.14-2.07 (m, 2H). MS ES+m/z 420 [M+H]⁺.

Example 13:3-fluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-Bromo-2-pyridyl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(dimethylcarbamoyl)-2-fluoro-phenyl]boronic acid, to give the productas a solid (26 mg, 14%). ¹H NMR (400 MHz, DMSO-d₆) δ=9.53 (s, 1H), 8.78(s, 1H), 8.58 (s, 1H), 8.42 (s, 1H), 8.36 (s, 1H), 7.86 (d, J=8.8 Hz,1H), 7.63 (t, J=8.0 Hz, 2H), 7.37 (d, 11.2 Hz, 1H), 7.33 (d, 9.6 Hz,1H), 7.0 (d, J=8.4 Hz, 1H), 3.88 (t, 6.8 Hz, 2H), 2.97 (br s, 6H),2.54-2.52 (m, 2H), 2.14-2.07 (m, 2H). MS ES+m/z 420 [M+H]⁺.

Example 14:2,5-difluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate10—2,5-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

4-Bromo-2,5-difluoro-N,N-dimethyl-benzamide (0.6 g, 2.27 mmol), B₂Pin₂(1.44 g, 5.68 mmol) and KOAc (0.67 g, 6.82 mmol) were taken up in1,4-dioxane (15 mL) and the mixture was degassed with argon for 10 min.PdCl₂ (dppf) DCM adduct (186 mg, 0.28 mmol) was added and the mixturestirred at 100° C. overnight. Water was added and the mixture extractedwith EtOAc. The combined organic layers were washed with brine, driedover Na₂SO₄, filtered, concentrated and purified on a silica gel columnto give the product (550 mg, 78%). MS ES+ m/z 230 [M+H]⁺ (boronic acid).

Step 2:2,5-difluoro-N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromo-2-pyridyl)amino]-3-pyridyl]pyrrolidin-2-one and2,5-difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,to give the product as a solid (49 mg, 18%). ¹H NMR (400 MHz, DMSO-d₆)δ=8.77 (s, 1H), 8.59 (s, 1H), 8.45 (s, 1H), 8.39 (s, 1H), 7.89 (d,J=4.0, 7.2 Hz, 1H), 7.60-7.57 (m, 1H), 7.42-7.39 (m, 1H), 7.0 (d, J=6.8Hz, 1H), 3.88 (t, 5.6 Hz, 2H), 3.02 (s, 3H), 2.91 (s, 3H), 2.54-2.52 (m,2H), 2.12-2.09 (m, 2H). MS ES+m/z 438 [M+H]⁺.

Example 15:N-methyl-4-[6-[[5-(2-oxopyrrolidin-1-yl)-3-pyridyl]amino]-3-pyridyl]benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromo-2-pyridyl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(methylcarbamoyl)phenyl]boronic acid, to give the product as a solid(100 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 8.78 (d, J=2.0Hz, 1H), 8.60-8.59 (m, 2H), 8.46 (d, J=3.0 Hz, 1H), 8.38 (d, J=2.4 Hz,1H), 8.01 (dd, J=2.4, 8.8 Hz, 1H), 7.92-7.90 (m, 2H), 7.78-7.76 (m, 2H),6.98 (d, J=8.8 Hz, 1H), 3.88 (t, J=7.0 Hz, 1H), 2.80 (d, J=4.4 Hz, 3H),2.54-2.50 (m, 2H), 2.14-2.07 (m, 2H). MS ES+m/z 388 [M+H]⁺.

Example 16:N,N-dimethyl-4-(4-methyl-6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

Step 1: Intermediate 11—5-Bromo-4-methyl-N-(3-pyridyl)pyridin-2-amine

The title compound was prepared as described in Intermediate 9, startingfrom 2,5-dibromo-4-methyl-pyridine and pyridin-3-amine and using DMF assolvent, to give the product as a solid (150 mg, 20%). MS ES+m/z 264[M+H]⁺.

Step 2:N,N-dimethyl-4-(4-methyl-6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 5-bromo-4-methyl-N-(3-pyridyl)pyridin-2-amine and[4-(dimethylcarbamoyl)phenyl]boronic acid, to give the product as asolid (90 mg, 21%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.26 (s, 1H), 8.81 (d,J=2.4 Hz, 1H), 8.23 (d, J=8.4 Hz, 1H), 8.09 (d, J=3.6 Hz, 1H), 8.03 (s,1H), 7.48-7.42 (m, 4H), 7.30-7.26 (m, 1H), 6.8 (s, 1H), 2.9 (br s, 6H),2.24 (s, 3H). MS ES+m/z 333 [M+H]⁺.

Example 17:4-(4-ethyl-6-(pyridin-3-ylamino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate12—4-(6-Amino-4-ethyl-3-pyridyl)-N,N-dimethyl-benzamide

The title compound was prepared as described in Example 10, startingfrom 5-bromo-4-ethyl-pyridin-2-amine and[4-(methylcarbamoyl)phenyl]boronic acid, to give the product as a solid(400 mg, 36%). MS ES+m/z 270 [M+H]⁺.

Step 2:4-(4-ethyl-6-(pyridin-3-ylamino)pyridin-3-yl)-N,N-dimethylbenzamide

Xantphos (22 mg, 0.04 mmol) and Pd₂(dba)₃ (17 mg, 0.02 mmol) was mixedin toluene (0.5 mL), stirred at 50° C. for 15 min and then transferredto a mixture of 4-(6-amino-4-ethyl-3-pyridyl)-N,N-dimethyl-benzamide(100 mg, 0.37 mmol), 3-bromopyridine (59 mg, 0.37 mmol) and NaOtBu (72mg, 0.75 mmol) in toluene (3 mL). The resulting mixture was stirred at90° C. overnight. When cooled to rt the reaction mixture was filteredthrough celite, concentrated and purified by preparative HPLC to givethe product as a solid (25 mg, 19%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.07 (t, J=7.41 Hz, 3H), 2.57 (q, J=7.36 Hz, 2H), 2.98 (br s, 6H), 6.84(s, 1H), 7.28 (dd, J=8.35, 4.57 Hz, 1H), 7.40 (m, J=7.88 Hz, 2H), 7.47(m, J=7.88 Hz, 2H), 7.99 (s, 1H), 8.09 (d, J=4.89 Hz, 1H), 8.24 (br d,J=9.46 Hz, 1H), 8.81 (d, J=2.52 Hz, 1H), 9.29 (s, 1H). MS ES+m/z 347[M+H]⁺.

Example 18: N,N-dimethyl-4-(5-(pyridin-3-ylamino)pyrazin-2-yl)benzamide

Step 1: Intermediate 13 Step 1:4-(5-Chloropyrazin-2-yl)-N,N-dimethyl-benzamide

The title compound was prepared as described in Intermediate 3, startingfrom 2-bromo-5-chloro-pyrazine and [4-(dimethylcarbamoyl)phenyl]boronicacid and stirring the mixture at 70° C. for 30 min, to give the productas a solid (250 mg, 92%). MS ES+m/z 262 [M+H]⁺.

Step 2: N,N-dimethyl-4-(5-(pyridin-3-ylamino)pyrazin-2-yl)benzamide

4-(5-Chloropyrazin-2-yl)-N,N-dimethyl-benzamide (150 mg, 0.57 mmol),pyridin-3-amine (80 mg, 0.85 mmol), KOtBu (110 mg, 0.98 mmol) andPEPPSI-IPr (7 mg, 0.01 mmol) were taken up in 1,4-Dioxane (1.5 mL) andthe resulting mixture was heated in a microwave reactor at 130° C. for 1h. When cooled to rt the mixture was diluted with EtOAc (10 mL), water(2 mL) and brine (5 mL). The organic layer was separated and the aqueouslayer extracted with EtOAc (2×10 mL). The combined organics were washedwith brine, dried over Na₂SO₄, filtered, concentrated and purified bypreparative HPLC to give the product as a solid (7 mg, 4%). ¹H NMR (500MHz, DMSO) δ 9.91 (s, 1H), 8.88 (d, J=2.2 Hz, 1H), 8.83 (s, 1H), 8.37(s, 1H), 8.30-8.21 (m, 1H), 8.19 (d, J=4.4 Hz, 1H), 8.07 (d, J=7.9 Hz,2H), 7.50 (d, J=8.2 Hz, 2H), 7.36 (dd, J=4.7, 8.2 Hz, 1H), 3.10-2.91 (m,6H). MS ES+m/z 320 [M+H]⁺.

Example 19:N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide

Step 1 Intermediate 14—1-(5-Amino-3-pyridyl)pyrrolidin-2-one

5-Bromopyridin-3-amine (10 g, 57.8 mmol), pyrrolidin-2-one (9 mL, 63.2mmol), K₂CO₃ (15 g, 115.6 mmol), CuI (1.1 g, 5.78 mmol) and DMEDA (1.3mL, 8.42 mmol) were taken up in 1,4-dioxane (100 mL) and the resultingmixture was refluxed overnight. When cooled to rt EtOAc was added andthe mixture filtered through celite. The filtrate was concentrated andpurified on a silica gel column to give the product as a solid (6 g,59%). MS ES+m/z 178 [M+H]⁺.

Step 2: Intermediate15—1-[5-[(5-Bromopyrazin-2-yl)amino]-3-pyridyl]pyrrolidin-2-one

The title compound was prepared as described in Intermediate 9, startingfrom 1-(5-Amino-3-pyridyl)pyrrolidin-2-one and 2,5-dibromopyrazine,using Cs₂CO₃ instead of NaOtBu, to give the product as a solid (110 mg,23%). MS ES+m/z 334 [M+H]⁺.

Step 3:N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromopyrazin-2-yl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(dimethylcarbamoyl)phenyl]boronic acid, to give the product as asolid (70 mg, 23%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.96 (s, 1H), 8.83 (dd,J=10.8, 1.6 Hz, 1H), 8.61 (t, J=2.2 Hz, 1H), 8.41 (d, J=2.8 Hz, 1H),8.38 (d, J=1.2 Hz, 1H), 8.07 (d, J=4.4 Hz, 2H), 7.50 (d, J=8.4 Hz, 2H),3.89 (t, J=6.8 Hz, 2H), 2.97 (bs, 6H), 2.55-2.52 (m, 2H), 2.15-2.07 (m,2H). MS ES+m/z 403 [M+H]⁺.

Example 20:2-fluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromopyrazin-2-yl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(dimethylcarbamoyl)-3-fluoro-phenyl]boronic acid, to give the productas a solid (96 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.02 (s, 1H), 8.89(d, J=0.8 Hz, 1H), 8.81 (d, J=2.0 Hz, 1H), 8.61 (t, J=2.2 Hz, 1H), 8.42(d, J=2.4 Hz, 1H), 8.37 (d, J=0.8 Hz, 1H), 7.96-7.89 (m, 2H), 7.47 (t,J=7.6 Hz, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.02 (s, 3H), 2.89 (s, 3H),2.55-2.52 (m, 2H), 2.15-2.07 (m, 2H). MS ES+m/z 421 [M+H]⁺.

Example 21:3-fluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromopyrazin-2-yl)amino]-3-pyridyl]pyrrolidin-2-one and[4-(dimethylcarbamoyl)-2-fluoro-phenyl]boronic acid, to give the productas a solid (33 mg, 11%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.03 (s, 1H), 8.80(d, J=2.0 Hz, 1H), 8.64 (d, J=2.0 Hz, 2H), 8.43 (d, J=2.4 Hz, 2H), 7.99(t, J=2.2 Hz, 1H), 7.42-7.35 (m, 2H), 3.89 (t, J=7.0 Hz, 2H), 3.00 (s,3H), 2.96 (s, 3H), 2.53-2.50 (m, 2H), 2.13-2.09 (m, 2H). MS ES+m/z 421[M+H]⁺.

Example 22:2,5-difluoro-N,N-dimethyl-4-(5-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 1-[5-[(5-bromopyrazin-2-yl)amino]-3-pyridyl]pyrrolidin-2-one and2,5-difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide,to give the product as a solid (91 mg, 30%). ¹H NMR (400 MHz, DMSO-d₆) δ10.10 (s, 1H), 8.80 (d, J=2.4 Hz, 1H), 8.67-8.64 (m, 2H), 8.44-8.42 (m,2H), 7.83-7.78 (m, 1H), 7.49-7.45 (m, 1H), 3.89 (t, J=7.2 Hz, 2H), 3.02(s, 3H), 2.91 (s, 3H), 2.55-2.53 (m, 2H), 2.15-2.07 (m, 2H). MS ES+m/z439 [M+H]⁺.

Example 23:4-(5-((5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)-N,N-dimethylbenzamide

Step 1: Intermediate 16—4-(5-Aminopyrazin-2-yl)-N,N-dimethyl-benzamide

The title compound was prepared as described in Intermediate 3, startingfrom 5-bromopyrazin-2-amine and [4-(dimethylcarbamoyl)phenyl]boronicacid and stirring the mixture at 90° C. for 2 h, to give the product asa solid (230 mg, 83%). MS ES+m/z 243 [M+H]⁺.

Step 2: Intermediate 17—1-(5-Bromo-3-pyridyl)-3-(2-chloroethyl)urea

2-Chloroethyl isocyanate (640 μL, 7.5 mmol) was added dropwise over 5min to a solution of 5-bromopyridin-3-amine (865 mg, 5 mmol) in toluene(10 mL) at 0° C. The resulting mixture was stirred at rt overnight. Theformed precipitate was filtered off, washed sequentially with toluene (3mL), pentane, (3 mL) and dried to give the product as a solid (1.3 g,93%). MS ES+m/z 278 [M+H]⁺.

Step 3: Intermediate 18—1-(5-Bromo-3-pyridyl)imidazolidin-2-one

A solution of 1-(5-bromo-3-pyridyl)-3-(2-chloroethyl)urea (1.3 g, 4.67mmol) in DMF (10 mL) was added slowly to suspension of NaH (60%, 268 mg,7 mmol) in THF (10 mL) at 0° C. The resulting mixture was stirred at rtfor 1 h. MeOH (5 mL) was added at 0° C. and the mixture concentrated.The resulting residue was partitioned between water (50 mL) and CHCl₃(20 mL). The organic layer was separated and the aqueous layer extractedwith CHCl₃ (2×20 mL). The combined organics were washed with water (20mL), sat. aq. NaHCO₃ (20 mL), dried over Na₂SO₄, and concentrated. Theresulting solid was triturated with EtOAc:pentane (1:3, 2×4 mL) followedby pentane (3 mL) and dried to give the product as a solid (850 mg,75%). MS ES+m/z 242 [M+H]⁺.

Step 4: Intermediate 19—1-Benzyl-3-(5-bromo-3-pyridyl)imidazolidin-2-one

1-(5-Bromo-3-pyridyl)imidazolidin-2-one (240 mg, 0.99 mmol) and TBAB(31.96 mg, 0.1 mmol) were taken up in toluene (5 mL). Aq. 2M NaOH (1.5mL) was added followed by chloromethyl benzene (126 μL, 1.09 mmol) andthe resulting mixture was stirred at 50° C. for 5 h. Additionalchloromethyl benzene (126 μL, 1.09 mmol) was added and stirringcontinued at 50° C. overnight. When cooled to rt EtOAc (5 mL) and water(5 mL) were added. The organic layer was separated and washed withbrine, dried over Na₂SO₄, filtered and concentrated to give the productas an oil (320 mg, 97%). MS ES+m/z 332 [M+H]⁺.

Step 5:4-(5-((5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyrazin-2-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Intermediate 9, startingfrom 4-(5-aminopyrazin-2-yl)-N,N-dimethyl-benzamide and1-benzyl-3-(5-bromo-3-pyridyl)imidazolidin-2-one, to give the product asa solid (21 mg, 10%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br d,J=11.98 Hz, 6H), 3.40-3.46 (m, 2H), 3.87-3.92 (m, 2H), 4.44 (s, 2H),7.30-7.41 (m, 5H), 7.51 (m, J=8.20 Hz, 2H), 8.09 (m, J=8.20 Hz, 2H),8.38 (s, 1H), 8.39 (s, 1H), 8.52-8.55 (m, 1H), 8.73 (d, J=2.21 Hz, 1H),8.84 (s, 1H), 9.91 (s, 1H). MS ES+m/z 494 [M+H]⁺.

Example 24:N,N-dimethyl-4-(6-((5-(N-methylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate20—N-(5-bromo-3-pyridyl)-N-methyl-methanesulfonamide

To a stirred solution of 5-bromo-N-methyl-pyridin-3-amine (518 mg, 2.77mmol) and TEA (0.58 mL, 4.15 mmol) in THF (5 mL) was addedmethanesulfonyl chloride (0.26 mL, 3.32 mmol) dropwise. The resultingmixture was stirred at 60° C. for 1 h. Additional TEA (0.58 mL, 4.15mmol) and methanesulfonyl chloride (0.26 mL, 3.32 mmol) were added andstirring continued for 30 min. Water (5 mL) was added and the THFremoved in vacuo. The resulting residue was extracted with EtOAc (2×10mL) and the combined organics were dried over Na₂SO₄, filtered andconcentrated to give the product as an oil (734 mg, quant.), which wasused in the next step without further purification. MS ES+m/z 267[M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(N-methylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 17, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide andN-(5-bromo-3-pyridyl)-N-methyl-methanesulfonamide, to give the productas a solid (24 mg, 13%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br s,6H), 3.06 (s, 3H), 3.31 (s, 3H), 7.00 (d, J=8.83 Hz, 1H), 7.50 (d,J=8.20 Hz, 2H), 7.75 (d, J=8.20 Hz, 2H), 8.03 (dd, J=8.67, 2.68 Hz, 1H),8.21 (d, J=2.52 Hz, 1H), 8.31 (t, J=2.21 Hz, 1H), 8.62 (d, J=2.52 Hz,1H), 8.82 (d, J=2.21 Hz, 1H), 9.59 (s, 1H). MS ES+m/z 426 [M+H]⁺.

Example 25:N,N-dimethyl-4-(6-((5-(N-methylcyclopropanesulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate21—N-(5-bromo-3-pyridyl)-N-methyl-cyclopropanesulfonamide

The title compound was prepared as described in Intermediate 20, usingcyclopropanesulfonyl chloride and purified by preparative HPLC, to givethe product (250 mg, 15%). MS ES+m/z 291 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(N-methylcyclopropanesulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

A mixture of XantPhos (40 mg, 0.07 mmol), Pd₂(dba)₃ (31 mg, 0.03 mmol),4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide (166 mg, 0.69 mmol),N-(5-bromo-3-pyridyl)-N-methyl-cyclopropanesulfonamide (200 mg, 0.69mmol) and NaOtBu (132 mg, 1.38 mmol) in 1,4-dioxane (10 mL) was heatedin a microwave reactor at 130° C. for 1 h. When cooled to rt the mixturewas diluted with EtOAc and filtered through celite. The filtrate waswashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by preparative HPLC to give the product as a solid (125 mg,40%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 8.78 (d, J=2.0 Hz, 1H),8.60 (d, J=2.4 Hz, 1H), 8.38 (t, J=2.2 Hz, 1H), 8.20 (d, J=2.0 Hz, 1H),8.01 (dd, J=7.8, 2.6 Hz, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.0 Hz,2H), 6.98 (d, J=8.4 Hz, 1H), 3.36-3.26 (m, 3H), 2.98 (bs, 6H), 2.83-2.77(m, 1H), 1.05-1.00 (m, 2H), 0.90-0.86 (m, 2H). MS ES+m/z 452 [M+H]⁺.

Example 26:N,N-dimethyl-4-(6-((5-(N-methylpropan-2-ylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate22—N-(5-bromo-3-pyridyl)-N-methyl-propane-2-sulfonamide

To a solution of N-(5-bromo-3-pyridyl)propane-2-sulfonamide (175 mg,0.63 mmol) in THF (2 mL) at 0° C. were added MeOH (0.12 mL, 3.14 mmol)and PPh₃ (197 mg, 0.75 mmol). After stirring for 10 min, DIAD (0.15 mL,0.75 mmol) was added and the resulting mixture was stirred at rtovernight. The reaction mixture was poured into water (10 mL) andextracted with EtOAc (2×25 mL). The combined organics were washed withbrine, dried over Na₂SO₄, filtered, concentrated and purified on asilica gel column eluted with 40-50% EtOAc in heptane to give theproduct as a solid (200 mg, 38%). MS ES+m/z 293 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(N-methylpropan-2-ylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25 to give theproduct as a solid (50 mg, 36%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (s,1H), 8.80 (d, J=2.4 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.34 (t, J=2.2 Hz,1H), 8.21 (d, J=2.4 Hz, 1H), 8.01 (dd, J=2.6, 8.6 Hz, 1H), 7.73 (d,J=8.0 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.8 Hz, 1H), 3.59-3.52(m, 1H), 3.48 (s, 3H), 2.97 (bs, 6H), 1.28 (d, J=6.8 Hz, 6H). MS ES+m/z454 [M+H]⁺.

Example 27:4-(6-((5-(N-isopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate23—N-(5-bromo-3-pyridyl)-N-isopropyl-methanesulfonamide

To a solution of 5-bromo-N-isopropyl-pyridin-3-amine (1 g, 4.65 mmol) inpyridine (10 mL) was added DMAP (113 mg, 0.93 mmol) and methanesulfonylchloride (1.14 mL, 13.95 mmol) at rt and the resulting mixture wasstirred at 60° C. overnight. When cooled to rt, the mixture was pouredinto water (10 mL) and extracted with EtOAc (2×25 mL). The combinedorganics were washed with brine, dried over Na₂SO₄, filtered,concentrated and purified by preparative HPLC to give the product (300mg, 19%). MS ES+m/z 293 [M+H]⁺.

Step 2:4-(6-((5-(N-isopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25 to give theproduct as a solid (160 mg, 34%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s,1H), 8.91 (d, J=2.0 Hz, 1H), 8.59 (d, J=2.4 Hz, 1H), 8.22 (d, J=2.0 Hz,1H), 8.05-8.01 (m, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),6.98 (d, J=8.4 Hz, 1H), 4.39-4.36 (m, 1H), 3.15 (s, 3H), 2.98 (s, 6H),1.14 (d, J=6.8 Hz, 6H). MS ES+m/z 454 [M+H]⁺.

Example 28:4-(6-((5-(N-cyclopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate24—N-(5-bromo-3-pyridyl)-N-cyclopropyl-methanesulfonamide

The title compound was prepared as described in Intermediate 23,starting from 5-bromo-N-cyclopropyl-pyridin-3-amine, to give the product(400 mg, 58%). MS ES+m/z 291 [M+H]⁺.

Step 2:4-(6-((5-(N-cyclopropylmethylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25 to give theproduct as a solid (180 mg, 38%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s,1H), 8.81 (d, J=2.0 Hz, 1H), 8.60 (d, J=2.4 Hz, 1H), 8.24 (s, 1H), 8.16(d, J=2.0 Hz, 1H), 8.01 (dd, J=8.8, 2.4 Hz, 1H), 7.73 (d, J=7.6 Hz, 2H),7.48 (d, J=7.6 Hz, 2H), 6.98 (d, J=8.4 Hz, 1H), 3.23-3.20 (m, 1H), 3.12(s, 3H), 2.98 (bs, 6H), 0.89-0.84 (m, 2H), 0.68-0.66 (m, 2H). MS ES+m/z452 [M+H]⁺.

Example 29:N,N-dimethyl-2-(6-(pyridin-3-ylamino)pyridin-3-yl)pyrimidine-5-carboxamide

Step 1: Intermediate 25—6-(3-Pyridylamino)pyridine-3-carbonitrile

The title compound was prepared as described in Intermediate 9, startingfrom 6-chloropyridine-3-carbonitrile and pyridine-3-amine, to give theproduct as a solid (1.05 g, 74%). MS ES+m/z 197 [M+H]⁺.

Step 2: Intermediate26—N-hydroxy-6-(3-pyridylamino)pyridine-3-carboxamidine

6-(3-Pyridylamino)pyridine-3-carbonitrile (500 mg, 2.55 mmol) was takenup in MeOH (10 mL) at rt and NaH (60%,146 mg, 3.82 mmol) was addedportion wise. The resulting mixture was stirred at rt overnight. Themixture was then stirred at 50° C. for 1 h, ammonium chloride (300 mg,5.6 mmol) was added and stirring continued at 65° C. for 4 h. Whencooled to rt 7M NH₃ in MeOH (3 mL) was added followed by hydroxylamineHCl (1.77 g, 25.5 mmol) and EtOH (5 mL). The resulting mixture wasstirred at 80° C. for 1 h. When cooled to rt the mixture wasconcentrated and the resulting residue was suspended in half-saturatedNaHCO₃ and the precipitate was filtered off, washed sequentially withwater (1.5 mL), 2-propanol (2 mL), pentane (3 mL) and dried to give theproduct as a solid (360 mg, 62%). MS ES+m/z 230 [M+H]⁺.

Step 3: Intermediate27—[[6-(3-Pyridylamino)pyridine-3-carboximidoyl]amino]acetate

Acetic anhydride (371 μL) 3.93 mmol) was added to a solution ofN-hydroxy-6-(3-pyridylamino)pyridine-3-carboxamidine (360 mg, 1.57 mmol)in AcOH (5 mL) at rt and the resulting mixture was stirred at rt for 30min. The mixture was concentrated and the resulting residue was taken upin sat. aq. NaHCO₃ (15 mL) and EtOAc (15 mL) and stirred at rt for 10min. The pH was checked to be above 7 and the formed precipitate wasfiltered off, washed with water and EtOAc and dried to give the productas a solid (280 mg, 66%). MS ES+m/z 272 [M+H]⁺.

Step 4: Intermediate 28—Ethyl-2-(diethoxymethyl)-3-hydroxy-prop-2-enoatesodium salt

NaH (60%, 500 mg, 13.0 mmol) was added to a solution of ethyl3,3-diethoxypropanoate (2 mL, 10.3 mmol) and ethyl formate (2 mL, 24.8mmol) in DME (10 mL) at rt under a nitrogen atmosphere. The resultingmixture was stirred at 50° C. for 10-15 min until hydrogen gas evolutioncommenced. The mixture was cooled with an ice/water bath and stirred onthe thawing cooling bath overnight. The mixture was concentrated and theresulting gum was triturated with Et₂O (3 mL) to give the product as agum (2.1 g, 85%), which was used in the next step.

Step 5: Intermediate 29—Ethyl2-[6-(3-pyridylamino)-3-pyridyl]pyrimidine-5-carboxylate

Zn (203 mg, 3.10 mmol) was added to a solution of[[6-(3-pyridylamino)pyridine-3-carboximidoyl]amino] acetate (280 mg,1.03 mmol) in AcOH (2 mL) at rt and the resulting mixture was stirred atrt for 5 h to give a thick suspension. More AcOH (3 mL) and Zn (203 mg,3.10 mmol) were added and stirring continued overnight. The mixture wasfiltered through celite and the filter cake rinsed with AcOH (1.5 mL).The filtrate was concentrated and the resulting residue (100 mg) wastaken up in DMF (2 mL). Ethyl-2-(diethoxymethyl)-3-hydroxy-prop-2-enoatesodium salt (135 mg, 0.563 mmol) was added and the resulting mixture wasstirred at 100° C. overnight. When cooled to rt water (6 mL) was addedand the mixture stirred for 30 min. The formed precipitate was filteredoff, washed sequentially with water, 2-propanol, pentane and dried togive the product as a solid (25 mg, 17%). MS ES+m/z 322 [M+H]⁺.

Step 6:N,N-dimethyl-2-(6-(pyridin-3-ylamino)pyridin-3-yl)pyrimidine-5-carboxamide

Ethyl 2-[6-(3-pyridylamino)-3-pyridyl]pyrimidine-5-carboxylate (25 mg,0.08 mmol) was taken up in THF (1 mL), MeOH (2 mL) and water (0.5 mL).LiOH hydrate (5 mg, 0.12 mmol) was added and the resulting mixture wasstirred at 50° C. for 2 h. When cooled the rt the mixture wasconcentrated and the resulting residue was taken up in SOCl₂ (1 mL, 13.7mmol) and THF (2 mL) and refluxed for 1 h. The mixture was concentratedand the residue taken up in THF (3 mL). Dimethylamine HCl (20 mg, 0.25mmol) and TEA (250 μL, 1.8 mmol) were added and the resulting mixturewas stirred at rt for 2 h. The mixture was concentrated and purified bypreparative HPLC to give the product as a solid (2.5 mg, 10%). ¹H NMR(500 MHz, METHANOL-d4) δ ppm 3.14 (br d, J=4.41 Hz, 6H), 6.94 (dd,J=8.83, 0.63 Hz, 1H), 7.35-7.41 (m, 1H), 8.14 (dd, J=4.89, 1.42 Hz, 1H),8.33 (ddd, J=8.35, 2.68, 1.58 Hz, 1H), 8.58 (dd, J=8.83, 2.21 Hz, 1H),8.85 (dd, J=2.52, 0.63 Hz, 1H), 8.88 (s, 2H), 9.27 (dd, J=2.21, 0.63 Hz,1H). MS ES+m/z 321 [M+H]⁺.

Example 30:4-(6-((5-cyanopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate 30—4-(6-Chloro-3-pyridyl)-N,N-dimethyl-benzamide

The title compound was prepared as described in Intermediate 3, startingfrom 4-iodo-N,N-dimethyl-benzamide and (6-chloro-3-pyridyl)boronic acidand stirring the mixture at 70° C. for 3 h, to give the product as asolid (475 mg, 67%). MS ES+m/z 261 [M+H]⁺.

Step 2:4-(6-((5-cyanopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-Chloro-3-pyridyl)-N,N-dimethyl-benzamide (120 mg, 0.46 mmol),5-aminopyridine-3-carbonitrile (55 mg, 0.46 mmol), Cs₂CO₃ (375 mg, 1.15mmol), Pd(OAc)₂ (10 mg, 0.05 mmol) and Xphos (44 mg, 0.09 mmol) weredissolved in DMF (3 mL) and the mixture was stirred at 120° C. for 1 h.When cooled to rt the mixture was filtered and the filtrate purified bypreparative HPLC to give the product as a solid (25 mg, 16%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 3H) 3.01 (s, 3H) 7.04 (d, 1H) 7.51(d, 2H) 7.76 (d, 2H) 8.07 (dd, 1H) 8.52 (s, 1H) 8.64-8.74 (m, 1H) 8.87(s, 1H) 8.97 (d, 1H) 9.91 (s, 1H). MS ES+m/z 344 [M+H]⁺.

Example 31:4-(6-((5-acetamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate31—N-[5-[(5-bromo-2-pyridyl)amino]-3-pyridyl]acetamide

The title compound was prepared as described in Example 9, starting from5-bromo-2-fluoro-pyridine and N-(5-amino-3-pyridyl)acetamide, to givethe product as a solid (467 mg, 59%). MS ES+m/z 307 [M+H]⁺.

Step 2:4-(6-((5-acetamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 10, startingfrom N-[5-[(5-bromo-2-pyridyl)amino]-3-pyridyl]acetamide and[4-(dimethylcarbamoyl)phenyl]boronic acid, to give the product as asolid (5 mg, 3%). ¹H NMR (500 MHz, DMSO-d₆+Methanol-d₄) δ ppm 2.08 (s,3H), 2.98 (m, J=12.00 Hz, 6H), 6.98 (d, J=8.83 Hz, 1H), 7.48 (d, J=8.51Hz, 2H), 7.72 (m, J=8.20 Hz, 2H), 7.98 (dd, J=8.83, 2.52 Hz, 1H), 8.31(d, J=2.21 Hz, 1H), 8.49 (t, J=2.21 Hz, 1H), 8.56 (d, J=2.21 Hz, 1H),8.68 (d, J=2.21 Hz, 1H). MS ES+m/z 376 [M+H]⁺.

Example 32:N,N-dimethyl-4-(6-(pyrimidin-5-ylamino)pyridin-3-yl)benzamide

Step 1: Intermediate 32—4-(6-Fluoro-3-pyridyl)-N,N-dimethyl-benzamide

The title compound was prepared as described in Example 10, startingfrom 5-bromo-2-fluoro-pyridine and [4-(dimethylcarbamoyl)phenyl]boronicacid, to give the product as a solid (1.17 g, 68%). MS ES+m/z 245[M+H]⁺.

Step 2: N,N-dimethyl-4-(6-(pyrimidin-5-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 9, starting from4-(6-fluoro-3-pyridyl)-N,N-dimethyl-benzamide and pyrimidin-5-amine, togive the product as a solid (15 mg, 9%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.92-3.04 (m, 6H), 7.01 (d, J=8.51 Hz, 1H), 7.49 (m, J=8.20 Hz, 2H),7.74 (m, J=8.20 Hz, 2H), 8.04 (dd, J=8.51, 2.52 Hz, 1H), 8.62 (d, J=2.52Hz, 1H), 8.73 (s, 1H), 9.19 (s, 2H), 9.64 (s, 1H). MS ES+m/z 320 [M+H]⁺.

Example 33:N,N-dimethyl-4-(6-((2-methylpyrimidin-5-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 9, starting from4-(6-fluoro-3-pyridyl)-N,N-dimethyl-benzamide and2-methylpyrimidin-5-amine, to give the product as a solid (20 mg, 11%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.55 (s, 3H), 2.96 (br s, 3H), 2.99 (brs, 3H), 6.96 (d, J=8.51 Hz, 1H), 7.48 (m, J=8.20 Hz, 2H), 7.72 (m,J=8.20 Hz, 2H), 8.00 (dd, J=8.83, 2.52 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H),9.05 (s, 2H), 9.50 (s, 1H). MS ES+m/z 320 [M+H]⁺.

Example 34:4-(6-((2-methoxypyrimidin-5-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 9, starting from4-(6-fluoro-3-pyridyl)-N,N-dimethyl-benzamide and2-methoxypyrimidin-5-amine, to give the product as a solid (45 mg, 23%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.96 (br s, 3H), 2.99 (br s, 3H), 3.89(s, 3H), 6.90 (d, J=8.83 Hz, 1H), 7.47 (d, J=8.51 Hz, 2H), 7.71 (d,J=8.20 Hz, 2H), 7.97 (dd, J=8.83, 2.52 Hz, 1H), 8.52 (d, J=2.52 Hz, 1H),8.92 (s, 2H), 9.32 (s, 1H). MS ES+m/z 350 [M+H]⁺.

Example 35:N,N-dimethyl-4-(6-((2-methylpyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 9, starting from4-(6-fluoro-3-pyridyl)-N,N-dimethyl-benzamide and2-methylpyridin-3-amine, to give the product as a solid (33 mg, 18%). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 2.47 (s, 3H), 2.96 (br s, 3H), 2.99 (br s,3H), 6.97 (d, J=8.83 Hz, 1H), 7.20 (dd, J=8.20, 4.73 Hz, 1H), 7.47 (m,J=8.20 Hz, 2H), 7.69 (m, J=8.20 Hz, 2H), 7.95 (dd, J=8.67, 2.36 Hz, 1H),8.09-8.12 (m, 1H), 8.14-8.16 (m, 1H), 8.46 (d, J=2.21 Hz, 1H), 8.51 (s,1H). MS ES+m/z 333 [M+H]⁺.

Example 36: N,N-dimethyl-4-(6-(pyrazin-2-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and 2-chloropyrazine,replacing NaOtBu with Cs₂CO₃ and heating at 160° C., to give the productas a solid (89 mg, 22%). ¹H NMR (500 MHz, CDCl₃) δ ppm 8.97 (s, 1H),8.47 (d, J=1.89 Hz, 1H), 8.24 (s, 2H), 8.11 (br d, J=8.51 Hz, 1H),7.99-8.05 (m, 1H), 7.57-7.62 (m, 2H), 7.53-7.57 (m, 2H), 3.15 (br s,3H), 3.05 (br s, 3H). MS ES+m/z 320 [M+H]⁺.

Example 37:5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-N,N-dimethylnicotinamide

Step 1 Intermediate 33—Ethyl5-[[5-[4-(dimethylcarbamoyl)phenyl]-2-pyridyl]amino]pyridine-3-carboxylate

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and ethyl5-bromopyridine-3-carboxylate, replacing NaOtBu with Cs₂CO₃ and heatingat 160° C., to give the product as a solid (472 mg, 41%). MS ES+m/z 391[M+H]⁺.

Step 2:5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-N,N-dimethylnicotinamide

Ethyl5-[[5-[4-(dimethylcarbamoyl)phenyl]-2-pyridyl]amino]pyridine-3-carboxylate(400 mg, 1.02 mmol) was taken up in MeOH (5 mL). Conc. HCl (4 mL) wasadded and the mixture refluxed overnight. When cooled to rt the mixturewas concentrated. An amount of the resulting residue,5-[[5-[4-(dimethylcarbamoyl)phenyl]-2-pyridyl]amino]pyridine-3-carboxylicacid (100 mg, 0.28 mmol) was taken up in DMF (3 mL), together withdimethylamine HCl (51 mg, 0.63 mmol) and HATU (240 mg, 0.63 mmol).Triethylamine (0.25 mL, 1.79 mmol) was added and the mixture was heatedin a microwave reactor at 60° C. for 1 h. The mixture was diluted withEtOAc (10 mL) and washed with sat. aq. NaHCO₃ (2×10 mL), brine, driedover MgSO₄, filtered, concentrated and purified by preparative HPLC togive the product as a solid (9 mg, 8%). ¹H NMR (500 MHz, CDCl₃) δ ppm9.01 (s, 1H), 8.71 (br s, 1H), 8.45 (d, J=2.21 Hz, 1H), 8.22 (s, 1H),7.76 (dd, J=8.67, 2.36 Hz, 1H), 7.48-7.57 (m, 4H), 7.05 (d, J=8.83 Hz,1H), 3.16 (br s, 6H), 3.08 (br s, 3H), 3.05 (br s, 3H). MS ES+m/z 390[M+H]⁺.

Example 38:N,N-dimethyl-4-(6-((5-(2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)pyrrolidin-2-one, replacing NaOtBu with Cs₂CO₃ andheating at 160° C., to give the product as a solid (43 mg, 25%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.06-2.17 (m, 2H), 2.52-2.56 (m, 2H), 2.94-3.04(m, 6H), 3.89 (t, J=7.09 Hz, 2H), 6.99 (d, J=8.51 Hz, 1H), 7.49 (d,J=7.88 Hz, 2H), 7.74 (d, J=8.20 Hz, 2H), 7.94-8.06 (m, 1H), 8.30-8.42(m, 1H), 8.55-8.62 (m, 2H), 8.77-8.84 (m, 1H), 9.52 (s, 1H). MS ES+m/z402 [M+H]⁺.

Example 39:4-(6-((5-methoxypyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and3-bromo-5-methoxy-pyridine, replacing NaOtBu with Cs₂CO₃ and heating at160° C., to give the product as a solid (21 mg, 6%). ¹H NMR (500 MHz,CDCl₃) δ ppm 3.02-3.10 (m, 3H), 3.15 (br s, 3H), 3.91 (s, 3H), 7.05 (brd, J=8.83 Hz, 1H), 7.48-7.52 (m, 2H), 7.53-7.59 (m, 2H), 7.73-7.79 (m,1H), 7.87 (s, 1H), 8.23-8.31 (m, 1H), 8.48 (d, J=1.89 Hz, 1H), 8.51 (brs, 1H). MS ES+m/z 349 [M+H]⁺.

Example 40:4-(6-((5-(1-cyanocyclopropyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)cyclopropane-1-carbonitrile, to give the product asa solid (240 mg, 84%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.57-1.61 (m,2H), 1.80-1.84 (m, 2H), 2.98 (br s, 6H), 6.99 (d, J=8.83 Hz, 1H), 7.48(m, J=8.20 Hz, 2H), 7.74 (m, J=8.20 Hz, 2H), 8.01 (dd, J=8.83, 2.52 Hz,1H), 8.07 (d, J=2.21 Hz, 1H), 8.27 (t, J=2.21 Hz, 1H), 8.61 (d, J=2.21Hz, 1H), 8.87 (d, J=2.52 Hz, 1H), 9.58 (s, 1H). MS ES+m/z 384 [M+H]⁺.

Example 41:4-(6-((5-(1-carbamoylcyclopropyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-[6-[[5-(1-Cyanocyclopropyl)-3-pyridyl]amino]-3-pyridyl]-N,N-dimethyl-benzamide(150 mg, 0.39 mmol) and K₂CO₃ (270 mg, 1.96 mmol) were taken up in DMSO(3 mL). 30% aq. H₂O₂ (400 μL, 3.92 mmol) was added and the resultingmixture was stirred at 50° C. for 3 h. MeOH (5 mL) was added and themixture allowed to cool to rt. The mixture was filtered and the filtratepurified by preparative HPLC to give the product as solid (21 mg, 13%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.00-1.05 (m, 2H), 1.36-1.42 (m, 2H),2.98 (br s, 6H), 6.50 (br s, 1H), 6.98 (d, J=8.55 Hz, 1H), 7.05 (br s,1H), 7.46-7.50 (m, 2H), 7.72-7.76 (m, 2H), 7.99 (dd, J=8.67, 2.68 Hz,1H), 8.09 (d, J=1.89 Hz, 1H), 8.20 (t, J=2.21 Hz, 1H), 8.61-8.65 (m,1H), 8.82 (d, J=2.52 Hz, 1H), 9.48 (s, 1H). MS ES+m/z 402 [M+H]⁺.

Example 42:N,N-dimethyl-4-(6-((1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)pyridin-3-yl)benzamide

Step 1 Intermediate 34—6-Bromo-1-methylsulfonyl-pyrrolo[3,2-b]pyridine

Triethylamine (0.42 mL, 3.05 mmol) was added to a solution of6-bromo-1H-pyrrolo[3,2-b]pyridine (300 mg, 1.52 mmol) andmethanesulfonyl chloride (0.18 mL, 2.28 mmol) in DCM at rt and theresulting mixture was stirred for 2 h. The mixture was concentrated andthe resulting residue was dissolved in EtOAc, washed with sat. aq.NaHCO₃, water, brine, dried over MgSO₄, filtered and concentrated togive the product as a solid (210 mg, 50%). MS ES+m/z 275 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((1-(methylsulfonyl)-1H-pyrrolo[3,2-b]pyridin-6-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and6-bromo-1-methylsulfonyl-pyrrolo[3,2-b]pyridine, replacing NaOtBu withCs₂CO₃ and heating at 120° C. for 2 h, to give the product as a solid(20 mg, 11%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br s, 6H), 3.47 (s,3H), 6.89 (d, J=3.78 Hz, 1H), 7.01 (d, J=8.51 Hz, 1H), 7.49 (d, J=8.20Hz, 2H), 7.72-7.78 (m, 3H), 8.02 (dd, J=8.83, 2.52 Hz, 1H), 8.60 (d,J=2.21 Hz, 1H), 8.81 (s, 1H), 8.88 (d, J=2.21 Hz, 1H), 9.63 (s, 1H). MSES+m/z 436 [M+H]⁺.

Example 43:4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate35—1-(7-Bromo-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)ethanone

7-Bromo-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazine (1 g, 4.65 mmol) and TEA(971 μL, 6.98 mmol) were taken up in 2-MeTHF (5 mL) and cooled to 0° C.Acetyl chloride (398 μL, 5.58 mmol) was added and the resulting mixturewas stirred at rt for 1 h. DCM (10 mL) was added followed by acetylchloride (398 μL, 5.58 mmol) and the mixture was stirred at rt for 1 h.EtOAc (20 mL) and water (10 mL) were added and the organic layerseparated. To the aqueous layer was added 2M aq. NaOH (5 mL) and EtOAc(10 mL) and the organic layer separated. The combined organics werewashed with sat. aq. NaHCO₃, brine, dried over Na₂SO₄, filtered andconcentrated. Recrystallization from 2-propanol gave the product as awhite solid (875 mg, 73%). MS ES+m/z 257 [M+H]⁺.

Step 2:4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(7-bromo-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)ethanone, replacingNaOtBu with Cs₂CO₃ and heating at 100° C. overnight, to give the productas a solid (3 mg, 2%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.31 (s, 3H),2.94-3.04 (s, 6H), 3.86-3.93 (m, 2H), 4.29-4.42 (m, 2H), 6.89 (d, J=8.83Hz, 1H), 7.48 (d, J=8.20 Hz, 2H), 7.71 (d, J=8.51 Hz, 2H), 7.94 (dd,J=8.83, 2.52 Hz, 1H), 8.33 (br s, 1H), 8.51 (d, J=2.21 Hz, 1H), 9.22 (brs, 1H). MS ES+m/z 418 [M+H]⁺.

Example 44:N,N-dimethyl-4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate36—7-Bromo-1-methylsulfonyl-2,3-dihydropyrido[2,3-b][1,4]oxazine

Methanesulfonyl chloride (94 μL, 1.21 mmol) was added to a solution of7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (130 mg, 0.6 mmol) andTEA (126 μL, 0.91 mmol) in 1,4-dioxane (2 mL) at rt and the mixture wasstirred for 5 h. Additional methanesulfonyl chloride (94 μL, 1.21 mmol)was added and the mixture was stirred at 60° C. overnight. The mixturewas concentrated and the residue was dissolved in EtOAc (60 mL), washedwith sat. aq. NaHCO₃ (20 mL), sat. aq. NH₄Cl (20 mL), brine, dried overMgSO₄, filtered and concentrated. Purification on a silica gel column,eluted with 20-60% EtOAc in heptane, gave the product as a solid (92 mg,52%). MS ES+m/z 293 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and7-bromo-1-methylsulfonyl-2,3-dihydropyrido[2,3-b][1,4]oxazine, replacingNaOtBu with Cs₂CO₃ and heating at 100° C. overnight, to give the productas a solid (16 mg, 12%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br s,6H), 3.22 (s, 3H), 3.82-3.86 (m, 2H), 4.36-4.40 (m, 2H), 6.90 (d, J=8.83Hz, 1H), 7.48 (d, J=8.51 Hz, 2H), 7.72 (d, J=8.20 Hz, 2H), 7.96 (dd,J=8.67, 2.36 Hz, 1H), 8.38 (d, J=2.52 Hz, 1H), 8.40 (d, J=2.52 Hz, 1H),8.51 (d, J=2.52 Hz, 1H), 9.29 (s, 1H). MS ES+m/z 454 [M+H]⁺.

Example 45: tert-butyl7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

Step 1: Intermediate 37—tert-Butyl7-bromo-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate

7-Bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (0.6 g, 2.79 mmol) andTEA (583 μL, 4.19 mmol) were taken up in 2-MeTHF (5 mL) and cooled to0′° C. tert-Butoxycarbonyl tert-butyl carbonate (1.22 g, 5.58 mmol) wasadded and the resulting mixture was stirred at rt overnight. EtOAc (20mL) and water (10 mL) were added and the organic layer separated. Thecombined organics were washed with sat. aq. NaHCO₃, brine, dried overNa₂SO₄, filtered and concentrated to give the product as a solid. (875mg, 99%). MS ES+m/z 315 [M+H]⁺.

Step 2: tert-butyl7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and tert-butyl7-bromo-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate and heatingat 100° C. for 3.5 h, to give the product as a solid (200 mg, 45%). ¹HNMR (500 MHz, DMSO-d₆) δ ppm 1.53 (s, 9H), 2.96-3.04 (m, 6H), 3.77-3.86(m, 2H), 4.24-4.35 (m, 2H), 6.85-6.93 (m, 1H), 7.46-7.51 (m, 2H),7.68-7.73 (m, 2H), 7.89-8.01 (m, 1H), 8.23-8.34 (m, 1H), 8.44-8.54 (m,1H), 8.58-8.72 (m, 1H), 9.12-9.27 (m, 1H). MS ES+m/z 476 [M+H]⁺.

Example 46:4-(6-((2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

tert-Butyl7-[[5-[4-(dimethylcarbamoyl)phenyl]-2-pyridyl]amino]-2,3-dihydropyrido[2,3-b][1,4]oxazine-1-carboxylate(200 mg, 0.42 mmol) was dissolved in DCM (5 mL). TFA (240 mg, 2.1 mmol)was added and the mixture stirred at rt overnight. The mixture wasconcentrated and purified by preparative HPLC to give the product as asolid (14 mg, 8%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 6H),3.22-3.29 (m, 2H), 4.19-4.25 (m, 2H), 6.09 (s, 1H), 6.84 (d, J=8.50 Hz,1H), 7.39 (d, J=2.21 Hz, 1H), 7.42-7.51 (m, 2H), 7.60 (d, J=2.21 Hz,1H), 7.67-7.71 (m, 2H), 7.89 (dd, J=8.83, 2.52 Hz, 1H), 8.45-8.52 (m,1H), 8.92 (s, 1H). MS ES+m/z 376 [M+H]⁺.

Example 47:N,N-dimethyl-4-(6-((5-(3-oxomorpholino)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate 38—4-(5-Bromo-3-pyridyl)morpholin-3-one

The title compound was prepared as described in Intermediate 14,starting from 3,5-dibromopyridine and morpholin-3-one to give theproduct as a solid (204 mg, 38%). MS ES+m/z 257 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(3-oxomorpholino)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and4-(5-bromo-3-pyridyl)morpholin-3-one, replacing NaOtBu with Cs₂CO₃ andheating at 100° C. overnight, to give the product as a solid (17 mg,21%). ¹H NMR (500 MHz, CDCl₃) δ ppm 3.05 (br s, 3H), 3.15 (br s, 3H),3.94 (br t, J=4.73 Hz, 2H), 4.11 (br t, J=4.73 Hz, 2H), 4.38 (s, 2H),7.30-7.36 (m, 1H), 7.48-7.60 (m, 4H), 7.82 (br dd, J=8.67, 2.05 Hz, 1H),8.42 (br s, 1H), 8.62 (s, 1H), 9.17 (br s, 1H), 9.34 (br s, 1H), 10.56(br s, 1H). MS ES+m/z 418 [M+H]⁺.

Example 48:N,N-dimethyl-4-(6-((5-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate 39—2-(5-Bromo-3-pyridyl)-1-morpholino-ethanone

Trimethylacetyl chloride (900 μL, 7.31 mmol) was added to a mixture of2-(5-bromo-3-pyridyl)acetic acid (1.5 g, 6.94 mmol) and diisopropylamine(1 mL, 7.14 mmol) in DCM (20 mL) at 0° C. The resulting mixture wasstirred at 0° C. for 30 min. Morpholine (750 μL) 8.57 mmol) was addedand the reaction mixture was stirred at rt for 2 h. The mixture waswashed with sat. aq. NH₄Cl (15 mL), sat. aq. NaHCO₃ (15 mL), dried overNa₂SO₄, filtered and concentrated to give the product as a brown oilwhich solidified upon standing (1.9 g, 96%). MS ES+m/z 285 [M+H]⁺.

Step 2: Intermediate 40—4-[2-(5-Bromo-3-pyridyl)ethyl]morpholine

Triethoxysilane (3.69 mL, 20 mmol) was added to suspension of zincacetate (245 mg, 1.33 mmol) in THF (10 mL) at rt and the resultingmixture was stirred at rt for 30 min. A solution of2-(5-bromo-3-pyridyl)-1-morpholino-ethanone (1.9 g, 6.66 mmol) in THF(15 mL) was added and the mixture was stirred at rt for 3 h. The mixturewas heated and stirred at 40° C. overnight. Aq. 1M NaOH (20 mL) wasadded, the mixture stirred vigorously for 3 h and extracted with EtOAc(3×10 mL). The combined organics were washed with brine, dried overNa₂SO₄, filtered and concentrated. The resulting residue was taken up inMeOH (20 mL) and sodium cyanoborohydride (837 mg, 13.3 mmol) was added,followed by acetic acid (0.5 mL) and the resulting mixture was stirredat rt overnight. The mixture was concentrated and the residue was takenup in 1M aq. HCl (10 mL) and EtOAc (5 mL). The aqueous layer wasseparated and the organic layer extracted with 1M aq. HCl (5 mL). To thecombined aqueous layers was added 2M aq. NaOH (10 mL) (pH checked to beabove 7) and EtOAc (5 mL). The organic layer was separated and theaqueous layer extracted with EtOAc (2×5 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated to givethe product as an oil (930 mg, 52%). MS ES+m/z 271 [M+H]⁺.

Step 3:N,N-dimethyl-4-(6-((5-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and4-[2-(5-bromo-3-pyridyl)ethyl]morpholine, to give the product as a solid(60 mg, 34%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.37-2.48 (m, 4H), 2.54(t, J=7.72 Hz, 2H), 2.74 (t, J=7.57 Hz, 2H), 2.94-3.04 (m, 6H), 3.58 (t,J=4.57 Hz, 4H), 6.97 (d, J=8.51 Hz, 1H), 7.48 (d, J=7.60 Hz, 2H), 7.72(d, J=7.58 Hz, 2H), 7.96-7.99 (m, 1H), 8.00-8.02 (m, 1H), 8.10 (t,J=2.05 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H), 8.71 (d, J=2.52 Hz, 1H), 9.38(s, 1H). MS ES+m/z 432 [M+H]⁺.

Example 49:4-(6-((5-(difluoromethoxy)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and3-bromo-5-(difluoromethoxy)pyridine and heating at 90° C. for 4 h, togive the product as a solid (39 mg, 31%). ¹H NMR (500 MHz, DMSO-d₆) δppm 2.98 (br d, J=10.09 Hz, 6H), 7.01 (d, J=8.74 Hz, 1H), 7.16-7.46 (m,1H), 7.47-7.51 (m, 2H), 7.72-7.76 (m, 2H), 8.01-8.05 (m, 2H), 8.34 (t,J=2.36 Hz, 1H), 8.62-8.68 (m, 2H), 9.72 (s, 1H). MS ES+m/z 385 [M+H]⁺.

Example 50:4-(6-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and heating at 80° C.for 2 days, to give the product as a solid (29 mg, 23%). ¹H NMR (500MHz, DMSO-d₆) δ ppm 2.93-3.02 (m, 6H), 4.24 (dt, J=3.78, 2.21 Hz, 2H),4.35 (dt, J=3.78, 2.21 Hz, 2H), 6.87 (d, J=8.57 Hz, 1H), 7.46-7.48 (m,2H), 7.68-7.71 (m, 2H), 7.87 (d, J=2.52 Hz, 1H), 7.92-7.96 (m, 2H), 8.52(d, J=2.21 Hz, 1H), 9.21 (s, 1H). MS ES+m/z 377 [M+H]⁺.

Example 51:N,N-dimethyl-4-(6-((6-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1 Intermediate 41—4-[2-(5-Bromo-2-pyridyl)ethyl]morpholine

5-Bromo-2-vinyl-pyridine (500 mg, 2.72 mmol), NaOtBu (522 mg, 5.434mmol) and morpholine (476 μL, 5.43 mmol) were taken up in THF (2.5 mL)and the mixture was stirred at 80° C. overnight. Additional morpholine(1.2 mL, 13.68 mmol) was added and stirring continued at 80° C.overnight. Water and DCM were added, the organic layer was separated andthe aqueous layer extracted with DCM. The combined organics were driedover MgSO₄, filtered, concentrated and purified on a silica gel columneluted with 0-100% EtOAc in heptane to give the product as an oil (423mg, 57%). MS ES+m/z 271 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((6-(2-morpholinoethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and4-[2-(5-bromo-2-pyridyl)ethyl]morpholine and heating at 90° C.overnight, to give the product as a solid (35 mg, 25%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.42 (br s, 4H), 2.59-2.67 (m, 2H), 2.77-2.88 (m, 2H),2.97 (br s, 6H), 3.57 (t, J=4.57 Hz, 4H), 6.93 (d, J=8.56 Hz, 1H), 7.21(d, J=8.51 Hz, 1H), 7.46-7.49 (m, 2H), 7.69-7.73 (m, 2H), 7.96 (dd,J=8.67, 2.68 Hz, 1H), 8.15 (dd, J=8.51, 2.84 Hz, 1H), 8.54 (d, J=2.21Hz, 1H), 8.70 (d, J=2.21 Hz, 1H), 9.32 (s, 1H). MS ES+m/z 432 [M+H]⁺.

Example 52:N,N-dimethyl-4-(6-((5-(N-methyl-2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate42—Trans-N-(5-bromo-3-pyridyl)-N-methyl-2-phenyl-cyclopropanecarboxamide

Trans-2-phenylcyclopropanecarboxylic acid (260 mg, 1.6 mmol) was takenup in SOCl₂ (1 mL, 13.7 mmol) and the resulting mixture was stirred at70° C. for 3 h. When cooled to rt the mixture was concentrated and theresulting residue was dissolved in 2-MeTHF (3 mL) and cooled to 0° C.5-bromo-N-methyl-pyridin-3-amine (200 mg, 1.07 mmol) was added followedby DIPEA (0.5 mL, 2.87 mmol) and the resulting mixture was stirred at rtfor 1.5 h. Water (5 mL) and EtOAc (5 mL) were added and the organiclayer separated. The aqueous layer was extracted with EtOAc (5 mL) andthe combined organics were washed with 0.4M aq. HCl (5 mL), sat. aq.NaHCO₃, brine, dried over Na₂SO₄, filtered and concentrated to give theproduct as an oil (385 mg, quant.). MS ES+m/z 331 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(N-methyl-2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide andtrans-N-(5-bromo-3-pyridyl)-N-methyl-2-phenyl-cyclopropanecarboxamideand heating at 95° C. overnight, to give the product as a solid (110 mg,36%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.23 (br s, 1H), 1.47-1.53 (m,1H), 1.58-1.79 (m, 1H), 2.38-2.43 (m, 1H), 2.98 (br s, 6H), 3.27 (br s,3H), 6.95 (d, J=8.51 Hz, 1H), 6.99-7.17 (m, 5H), 7.49 (d, J=8.20 Hz,2H), 7.72 (d, J=8.51 Hz, 2H), 7.99 (dd, J=8.83, 2.52 Hz, 1H), 8.08 (d,J=1.89 Hz, 1H), 8.43 (br s, 1H), 8.54 (d, J=2.21 Hz, 1H), 8.64 (d,J=2.21 Hz, 1H), 9.58 (s, 1H). MS ES+m/z 492 [M+H]⁺.

Example 53:N,N-dimethyl-4-(6-((5-(1-oxoisoindolin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate43—4-[6-[(5-Bromo-3-pyridyl)amino]-3-pyridyl]-N,N-dimethyl-benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and3,5-dibromopyridine and heating at 90° C. for 2 h, to give the productas a solid (180 mg, 27%). MS ES+m/z 397 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(1-oxoisoindolin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

4-[6-[(5-Bromo-3-pyridyl)amino]-3-pyridyl]-N,N-dimethyl-benzamide (105mg, 0.26 mmol), isoindolin-1-one (60 mg, 0.45 mmol), CuI (10 mg, 0.05mmol), DMEDA (0.02 mL, 0.16 mmol) and K₂CO₃ (73 mg, 0.53 mmol) weresuspended in 1,4-dioxane (3 mL) and stirred at 100° C. overnight. Thereaction mixture was filtered, the solid washed with EtOAc and MeOH, andthe filtrate concentrated. The resulting residue was washed with aqueousammonia (25%) and triturated with acetone to give the product as a solid(4 mg, 3%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 3.00 (br s, 6H), 5.11 (s,2H), 7.04 (d, J=8.51 Hz, 1H), 7.48-7.52 (m, 2H), 7.56-7.62 (m, 1H),7.71-7.74 (m, 2H), 7.76 (d, J=8.51 Hz, 2H), 7.84 (d, J=7.57 Hz, 1H),8.03 (dd, J=8.67, 2.68 Hz, 1H), 8.63 (d, J=2.52 Hz, 2H), 8.82 (d, J=2.21Hz, 1H), 8.90 (t, J=2.36 Hz, 1H), 9.58 (s, 1H). MS ES+m/z 450 [M+H]⁺.

Example 54:4-(6-((1-benzyl-6-oxo-1,6-dihydropyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A solution of Brettphos (33 mg, 0.06 mmol) and Pd₂(dba)₃ (19 mg, 0.02mmol) in toluene (1 mL) was degassed with nitrogen and stirred at 50° C.for 30 min. It was then transferred to a mixture of4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide (100 mg, 0.41 mmol),1-benzyl-5-bromo-pyridin-2-one (109 mg, 0.41 mmol) and NaOtBu (80 mg,0.83 mmol) in toluene (4 mL) and DMF (1 mL) and the resulting mixturewas stirred at 90° C. overnight. When cooled to rt the mixture wasdiluted with EtOAc, washed with sat. aq. NH₄Cl, concentrated andpurified by preparative HPLC to give the product as a solid (35 mg,20%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 6H), 5.13 (s, 2H),6.49 (d, J=9.77 Hz, 1H), 6.77 (d, J=8.83 Hz, 1H), 7.29-7.39 (m, 5H),7.46 (m, J=8.20 Hz, 2H), 7.55 (dd, J=9.77, 2.84 Hz, 1H), 7.68 (m, J=8.20Hz, 2H), 7.89 (dd, J=8.83, 2.52 Hz, 1H), 8.23 (d, J=2.84 Hz, 1H), 8.44(d, J=2.52 Hz, 1H), 8.80 (s, 1H). MS ES+m/z 450 [M+H]⁺.

Example 55:4′-((5-(2-(dimethylamino)-2-oxoethyl)pyridin-3-yl)amino)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide

Step 1: Intermediate 44—2-(5-Bromo-3-pyridyl)-N,N-dimethyl-acetamide

The title compound was prepared as described in Intermediate 39, usingdimethylamine instead of morpholine, to give the product as an oil (335mg, 85%). MS ES+m/z 243 [M+H]⁺.

Step 2:4′-((5-(2-(dimethylamino)-2-oxoethyl)pyridin-3-yl)amino)-N,N-dimethyl-[1,1′-biphenyl]-4-carboxamide

Brettphos (22 mg, 0.04 mmol), Pd₂(dba)₃ (19 mg, 0.02 mmol) and K₂CO₃ (86mg, 0.62 mmol) were taken up in tBuOH (2 mL) and stirred at 50° C. for15 min. 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide (100 mg, 0.41 mmol)and a solution of 2-(5-bromo-3-pyridyl)-N,N-dimethyl-acetamide (131 mg,0.54 mmol) in tBuOH (1 mL) were added and the resulting mixture wasrefluxed overnight. When cooled to rt the mixture was filtered,concentrated and purified by preparative HPLC to give the product as asolid (86 mg, 51%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.86 (s, 3H), 2.98(br s, 6H), 3.06 (s, 3H), 3.72 (s, 2H), 6.96 (d, J=8.83 Hz, 1H), 7.48(m, J=8.20 Hz, 2H), 7.72 (m, J=8.20 Hz, 2H), 7.96-8.01 (m, 2H),8.01-8.05 (m, 1H), 8.57 (d, J=2.52 Hz, 1H), 8.79 (d, J=2.52 Hz, 1H),9.39 (s, 1H). MS ES+m/z 404 [M+H]⁺.

Example 56:N,N-dimethyl-4-(6-((5-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate45—2-(5-Bromo-3-pyridyl)-N-(3-pyridylmethyl)acetamide

The title compound was prepared as described in Intermediate 39, using3-pyridylmethanamine instead of morpholine, to give the product as anoil (213 mg, 73%). MS ES+m/z 306 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(2-oxo-2-((pyridin-3-ylmethyl)amino)ethyl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 55, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and2-(5-bromo-3-pyridyl)-N-(3-pyridylmethyl)acetamide, to give the productas a solid (58 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s,6H), 3.52 (s, 2H), 4.32 (d, J=5.67 Hz, 2H), 6.97 (d, J=8.83 Hz, 1H),7.32 (dd, J=7.88, 4.73 Hz, 1H), 7.49 (m, J=8.20 Hz, 2H), 7.66 (br d,J=7.88 Hz, 1H), 7.73 (m, J=8.20 Hz, 2H), 7.97-8.01 (m, 1H), 8.01-8.04(m, 1H), 8.15 (s, 1H), 8.44 (d, J=5.23 Hz, 1H), 8.50 (s, 1H), 8.57 (d,J=2.52 Hz, 1H), 8.69 (br t, J=5.83 Hz, 1H), 8.77 (d, J=2.21 Hz, 1H),9.41 (s, 1H). MS ES+m/z 467 [M+H]⁺.

Example 57:(S)-4-(6-((5-(4-isopropyl-2,5-dioxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 2: Intermediate46—(5S)-3-(5-bromo-3-pyridyl)-5-isopropyl-imidazolidine-2,4-dione

Methyl (2S)-2-isocyanato-3-methyl-butanoate (350 μL, 2.36 mmol) wasadded to a suspension of 5-bromopyridin-3-amine (350 mg, 2.02 mmol) intoluene (3 mL) at 0° C. The resulting mixture was stirred at rt for 2days. The mixture was placed in refrigerator for 2 h, pentane (3 mL) wasadded and the precipitate was filtered off, washed with pentane (3 mL)and dried to give the product as a solid. MS ES+m/z 298 [M+H]⁺.

Step 2:(S)-4-(6-((5-(4-isopropyl-2,5-dioxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 55, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and(5S)-3-(5-bromo-3-pyridyl)-5-isopropyl-imidazolidine-2,4-dione, to givethe product as a solid (11 mg, 6%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 0.92(d, J=6.94 Hz, 3H), 1.04 (d, J=6.94 Hz, 3H), 2.16 (m, 1H), 2.98 (br s,6H), 4.20 (d, J=3.15 Hz, 1H), 7.00 (d, J=8.51 Hz, 1H), 7.48 (d, J=8.20Hz, 2H), 7.74 (d, J=8.20 Hz, 2H), 8.02 (dd, J=8.51, 2.52 Hz, 1H), 8.10(d, J=1.89 Hz, 1H), 8.26 (t, J=2.21 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H),8.63 (s, 1H), 8.91 (d, J=2.52 Hz, 1H), 9.64 (s, 1H). MS ES+m/z 459[M+H]⁺.

Example 58:4-(6-((3,4-dihydro-2H-pyrano[2,3-b]pyridin-6-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 55, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and6-bromo-3,4-dihydro-2H-pyrano[2,3-b]pyridine, and replacing tBuOH for1,4-dioxane and K₂CO₃ for Cs₂CO₃, to give the product as a solid (99 mg,64%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.87-1.97 (m, 2H), 2.80 (t, J=6.46Hz, 2H), 2.99 (br s, 6H), 4.18-4.28 (m, 2H), 6.83-6.89 (m, 1H),7.45-7.49 (m, 2H), 7.68-7.73 (m, 2H), 7.93 (td, J=4.33, 2.68 Hz, 2H),8.20 (d, J=2.84 Hz, 1H), 8.50-8.52 (m, 1H), 9.10 (s, 1H). MS ES+m/z 375[M+H]⁺.

Example 59:4-(6-((1-acetyl-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate47—N-[5-bromo-2-[2-hydroxyethyl(methyl)amino]-3-pyridyl]acetamide

2-(Methylamino)ethanol (840 μL, 10.5 mmol) was added to a suspension of5-bromo-2-chloro-3-nitro-pyridine (2.37 g, 10 mmol) and K₂CO₃ (2.07 g,15 mmol) in EtOH (20 mL) at rt. The resulting mixture was stirred at 70°C. for 30 min. The temperature was lowered to 40° C. and a solution ofsodium dithionite (7 g, 40.2 mmol) in water (20 mL) was added slowly.The mixture was stirred at 40° C. for 30 min and then at 50° C. for 15min. More sodium dithionite (2.5 g, 14.36 mmol) dissolved in water (10mL) was added and the mixture was stirred at 50° C. for 1 h. Sodiumdithionite (5 g, 28.72 mmol) was added and the mixture was stirred at50° C. for 30 min. The mixture was concentrated to about half the volumeand a minimal amount of water was added to give a clear solution. Themixture was extracted with EtOAc (3×10 mL) and the combined organicswere washed with brine, dried over Na₂SO₄, filtered and concentrated.The resulting residue (1 g) was taken up in DCM (15 mL) and pyridine (1mL, 12.4 mmol). Acetic anhydride (400 μL, 4.23 mmol) was added and theresulting mixture was stirred at 40° C. for 2 days. The mixture wasdiluted with toluene (5 mL), concentrated and purified on a silica gelcolumn eluted with 0-100% EtOAc in Heptane to give the product as a gum(580 mg, 20%). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.56 (br s, 1H), 2.21 (s,3H), 2.85 (s, 3H), 3.07-3.17 (m, 2H), 3.89-3.97 (m, 2H), 8.06 (d, J=2.52Hz, 1H), 8.89 (d, J=2.21 Hz, 1H), 8.95 (br s, 1H). MS ES+m/z 288 [M+H]⁺.

Step 2: Intermediate48—1-(7-Bromo-4-methyl-2,3-dihydropyrido[2,3-b]pyrazin-1-yl)ethenone

DIAD (436 μL, 2.21 mmol) was added dropwise to a solution ofN-[5-bromo-2-[2-hydroxyethyl(methyl)amino]-3-pyridyl]acetamide (580 mg,2.01 mmol) and triphenylphosphine (581 mg, 2.21 mmol) in THF (20 mL) atrt. The resulting mixture was stirred at rt for 30 min. The mixture wasconcentrated and purified on a silica gel column eluted with 0-60% EtOAcin heptane to give the product as a gum (485 mg, 89%). MS ES+m/z 270[M+H]⁺.

Step 3:4-(6-((1-acetyl-4-methyl-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-Amino-3-pyridyl)-N,N-dimethyl-benzamide (120 mg, 0.5 mmol),1-(7-bromo-4-methyl-2,3-dihydropyrido[2,3-b]pyrazin-1-yl)ethanone (134mg, 0.5 mmol), Brettphos Pd G3 (22 mg, 0.03 mmol) and Cs₂CO₃ (450 mg,1.38 mmol) were taken up in tBuOH (5 mL) and stirred at 90° C. for 5 h.The mixture was concentrated and the resulting residue was taken up inEtOAc (5 mL) and water (3 mL). The organic layer was separated and theaqueous layer extracted with EtOAc (2×5 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered, concentrated andpurified by preparative HPLC to give the product as a solid (65 mg,30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.23 (s, 3H), 2.98 (br s, 6H),3.05 (s, 3H), 3.40 (br t, J=4.89 Hz, 2H), 3.80-3.85 (m, 2H), 6.78 (d,J=8.43 Hz, 1H), 7.44-7.49 (m, 2H), 7.66-7.70 (m, 2H), 7.87 (dd, J=8.67,2.68 Hz, 1H), 8.12 (br s, 1H), 8.42-8.46 (m, 1H), 8.87 (s, 1H). MSES+m/z 431 [M+H]⁺.

Example 60:N,N-dimethyl-4-(6-((6-morpholinopyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 59, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and4-(5-iodo-2-pyridyl)morpholine, to give the product as a solid (38 mg,23%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 6H), 3.33-3.38 (m,4H), 3.70-3.74 (m, 4H), 6.80-6.87 (m, 2H), 7.44-7.48 (m, 2H), 7.66-7.71(m, 2H), 7.89 (dd, J=8.67, 2.68 Hz, 1H), 7.94 (dd, J=8.98, 2.68 Hz, 1H),8.40 (d, J=2.21 Hz, 1H), 8.46 (dd, J=2.52, 0.63 Hz, 1H), 8.96 (s, 1H).MS ES+m/z 403 [M+H]⁺.

Example 61:N,N-dimethyl-4-(6-((2-methyloxazolo[4,5-b]pyridin-6-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 59, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and6-bromo-2-methyl-oxazolo[4,5-b]pyridine, replacing tBuOH for 1,4-dioxaneand stirring at 100° C. for 2 days, to give the product as a solid (16mg, 4%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.65 (s, 3H), 2.97-3.02 (m,6H), 6.97-7.03 (m, 1H), 7.49 (s, 1H), 7.51 (s, 1H), 7.73 (s, 1H), 7.75(s, 1H), 8.00-8.05 (m, 1H), 8.54 (s, 1H), 8.60-8.62 (m, 1H), 8.82 (d,J=2.52 Hz, 1H), 9.71 (s, 1H). MS ES+m/z 374 [M+H]⁺.

Example 62:4-(6-([1,3]dioxolo[4,5-b]pyridin-6-ylamino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 59, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and6-bromo-[1,3]dioxolo[4,5-b]pyridine, replacing tBuOH for 1,4-dioxane andstirring at 100° C. overnight, to give the product as a solid (19 mg,23%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 6H) 6.13 (s, 2H) 6.88(d, J=8.83 Hz, 1H) 7.48 (d, J=7.61 Hz, 2H) 7.70 (s, 1H) 7.71 (s, 1H)7.77 (d, J=2.21 Hz, 1H) 7.83 (d, J=1.89 Hz, 1H) 7.95 (dd, J=8.67, 2.68Hz, 1H) 8.52 (d, J=2.52 Hz, 1H) 9.21 (s, 1H). MS ES+m/z 363 [M+H]⁺.

Example 63:N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzenesulfonamide

Step 1: Intermediate49—4-(6-Chloro-3-pyridyl)-N,N-dimethyl-benzenesulfonamide

2-Chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1.39g, 5.82 mmol), 4-iodo-N,N-dimethyl-benzenesulfonamide (1.51 g, 4.85mmol), K₂CO₃ (1.68 g, 12.13 mmol) and PdCl₂(Amphos) (0.14 g, 0.2 mmol)were dissolved in 1,4-dioxane (5 mL) and water (2 mL) and the mixturewas stirred at 95° C. for 2 h. Water and EtOAc was added and the mixturewas extracted. The organic layer was concentrated and the residue wasrecrystallized from EtOH to give the product as a solid (0.25 g, 17%).MS ES+m/z 297 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzenesulfonamide

The title compound was prepared as described in Example 30, startingfrom 4-(6-chloro-3-pyridyl)-N,N-dimethyl-benzenesulfonamide andpyridine-3-amine, to give the product as a solid (26 mg, 11%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.66 (s, 6H) 7.00 (d, 1H) 7.33 (dd, 1H) 7.81(m, 2H) 7.96 (m, 2H) 8.06 (dd, 1H) 8.15 (dd, 1H) 8.27 (br d, 1H) 8.65(d, 1H) 8.86 (d, 1H) 9.53 (s, 1H). MS ES+m/z 355 [M+H]⁺.

Example 64:N-methyl-N-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)acetamide

Step 1: Intermediate50—N-[4-(6-chloro-3-pyridyl)phenyl]-N-methyl-acetamide

The title compound was prepared as described in Intermediate 3, startingfrom N-(4-bromophenyl)-N-methyl-acetamide and(6-chloro-3-pyridyl)boronic acid, to give the product as a solid (1.33g, 58%). MS ES+m/z 261 [M+H]⁺.

Step 2:N-methyl-N-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)acetamide

N-[4-(6-chloro-3-pyridyl)phenyl]-N-methyl-acetamide (730 mg, 2.8 mmol),Cs₂CO₃ (1.4 g, 4.2 mmol),2-(2′-Di-tert-butylphosphine)biphenylpalladium(II) acetate (65 mg, 0.14mmol), pyridin-3-amine (350 mg, 3.72 mmol) and TEA (0.19 mL, 1.4 mmol)were taken up in 1,4-dioxane (15 mL), the resulting mixture was degassedwith nitrogen for 5 min and stirred at 90° C. overnight. NaOtBu (538 mg,5.6 mmol) and 2-(2′-Di-tert-butylphosphine)biphenylpalladium(II) acetate(65 mg, 0.14 mmol) were added and stirring continued at 90° C. for 4 h.When cooled to rt the mixture was diluted with EtOAc (10 mL), brine (10mL) and water (5 mL). The organic layer was separated and the aqueouslayer extracted with EtOAc (2×10 mL). The combined organics were washedwith brine, filtered, concentrated and purified by preparative HPLC togive the product as a solid (36 mg, 4%). ¹H NMR (500 MHz, DMSO-d₆)δ=9.42 (br s, 1H), 8.84 (d, J=2.5 Hz, 1H), 8.61-8.51 (m, 1H), 8.31-8.22(m, 1H), 8.11 (dd, J=1.3, 4.4 Hz, 1H), 7.97 (dd, J=2.2, 8.5 Hz, 1H),7.72 (br d, J=7.3 Hz, 2H), 7.40 (br d, J=7.9 Hz, 2H), 7.36-7.27 (m, 1H),6.96 (d, J=8.8 Hz, 1H), 3.17 (s, 3H), 1.82 (br s, 3H). MS ES+m/z 319[M+H]⁺.

Example 65:5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N-(pyridin-3-yl)pyridin-2-amine

Step 1: Intermediate 51—3-(4-Bromophenyl)-4-methyl-1,2,4-triazole

4-Bromobenzohydrazide 650 mg, 3.02 mmol) and DMFDMA (0.5 mL, 3.76 mmol)were taken up in DMF (1.5 mL) and the resulting mixture was heated in amicrowave reactor at 130° C. for 1 h. When cooled to rt33% MeNH₂ (1.5mL, 12.05 mmol) in EtOH was added followed by careful addition of AcOH(1 mL, 17.48 mmol). The resulting mixture was heated in a microwavereactor at 130° C. for 30 min. When cooled to rt the mixture was pouredinto water (15 mL) and kept in refrigerator overnight. The formedprecipitate was filtered off and discarded. The pH of the filtrate wasadjusted >7 using 2M aq. NaOH and then extracted with EtOAc (3×10 m).The combined organics were washed with brine, dried over Na₂SO₄,filtered and concentrated to give the product as a solid (440 mg, 61%).MS ES+ m/z 238 [M+H]⁺.

Step 2: Intermediate52—2-Chloro-5-[4-(4-methyl-1,2,4-triazol-3-yl)phenyl]pyridine

The title compound was prepared as described in Intermediate 4, startingfrom 3-(4-bromophenyl)-4-methyl-1,2,4-triazole and(6-chloro-3-pyridyl)boronic acid, replacing 1,4-dioxane for n-BuOH andstirring the mixture at 90° C. for 2.5 h, to give the product as a solid(250 mg, 55%). MS ES+m/z 271 [M+H]⁺.

Step 3:5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)-N-(pyridin-3-yl)pyridin-2-amine

The title compound was prepared as described in Example 18, startingfrom 2-chloro-5-[4-(4-methyl-1,2,4-triazol-3-yl)phenyl]pyridine andpyridine-3-amine and replacing 1,4-dioxane for DMF, to give the productas a solid (15 mg, 10%). ¹H NMR (500 MHz, DMSO-d₆) δ=9.47 (s, 1H), 8.86(d, J=2.5 Hz, 1H), 8.64-8.63 (m, 1H), 8.60 (s, 1H), 8.28 (br d, J=8.5Hz, 1H), 8.14 (dd, J=1.1, 4.6 Hz, 1H), 8.05 (dd, J=2.5, 8.8 Hz, 1H),7.89-7.83 (m, 4H), 7.33 (dd, J=4.7, 8.2 Hz, 1H), 7.00 (d, J=8.5 Hz, 1H),3.80 (s, 3H). MS ES+m/z 329 [M+H]⁺.

Example 66:(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)(pyrrolidin-1-yl)methanone

The title compound was prepared as described in Example 10, startingfrom 5-bromo-N-(3-pyridyl)pyridin-2-amine and[4-(pyrrolidine-1-carbonyl)phenyl]boronic acid, to give the product as asolid (42 mg, 30%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.82-1.94 (m, 4H),3.44-3.54 (m, 4H), 6.95-7.02 (m, 1H), 7.29-7.34 (m, 1H), 7.59-7.63 (m,2H), 7.71-7.75 (m, 2H), 7.97-8.03 (m, 1H), 8.10-8.15 (m, 1H), 8.24-8.31(m, 1H), 8.48-8.63 (m, 1H), 8.75-8.93 (m, 1H), 9.40-9.52 (m, 1H). MSES+m/z 345 [M+H]⁺.

Example 67:N-benzyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

Step 1: Intermediate 53 —: [4-[Benzyl(methyl)carbamoyl]phenyl]boronicacid

4-Boronobenzoic acid (1 g, 6.03 mmol) was dissolved in DMF (5 mL). HATU(2.8 g, 7.41 mmol) and DIPEA (5.38 mL, 30.88 mmol) were added and theresulting mixture was stirred at rt for 10 min.N-methyl-1-phenyl-methanamine (1.59 mL, 12.4 mmol) was added and themixture was stirred at rt for 2.5 h. Water (50 mL) and EtOAc (50 mL)were added, the organic layer separated and washed with half sat. aq.NH₄Cl (2×50 mL), water (2×50 mL), brine, dried over Na₂SO₄ andconcentrated to give the product as a solid (1.49 g, 90%). MS ES+m/z 270[M+H]⁺.

Step 2: N-benzyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 10, startingfrom 5-bromo-N-(3-pyridyl)pyridin-2-amine and[4-[benzyl(methyl)carbamoyl]phenyl]boronic acid, to give the product asa solid (55 mg, 34%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 9.44 (1H, br s)8.83 (1H, br s) 8.57 (1H, br s) 8.26 (1H, br d) 8.11 (1H, m) 7.98 (1H,br s) 7.74 (2H, br s) 7.53 (2H, br s) 7.35-7.42 (3H, m) 7.30 (2H, dd)7.22 (1H, br s) 6.92-7.01 (1H, m) 4.69 (1H, br s) 4.55 (1H, br s) 2.89(3H, br s). MS ES+m/z 395 [M+H]⁺.

Example 68:N-ethyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

Step 1: Intermediate 54—Methyl 4-[6-(3-pyridylamino)-3-pyridyl]benzoate

The title compound was prepared as described in Example 10, startingfrom 5-bromo-N-(3-pyridyl)pyridin-2-amine and(4-methoxycarbonylphenyl)boronic acid, to give the product as a solid(412 mg, 70%). MS ES+m/z 306 [M+H]⁺.

Step 2: Intermediate 55—4-[6-(3-Pyridylamino)-3-pyridyl]benzoic acid

Methyl 4-[6-(3-pyridylamino)-3-pyridyl]benzoate (412 mg, 1.35 mmol) wastaken up in MeOH (20 mL) and water (2 mL). LiOH hydrate (283 mg, 6.75mmol) was added and the reaction mixture was refluxed overnight. Whencooled to rt the mixture was concentrated and 1M aq. HCl (50 mL) wasadded. The formed precipitate was filtered off and dried to give theproduct as a solid (342 mg, 87%). MS ES+m/z 292 [M+H]⁺.

Step 3: N-ethyl-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Intermediate 53,starting from 4-[6-(3-pyridylamino)-3-pyridyl]benzoic acid andN-methylethylamine. Purification by preparative HPLC gave the product asa solid (63 mg, 55%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.11 (br s, 3H),2.95 (br s, 3H), 3.22-3.32 (m, 1H), 3.35-3.54 (m, 1H), 6.98 (dd, J=8.83,0.63 Hz, 1H), 7.32 (dd, J=8.35, 4.57 Hz, 1H), 7.46 (br s, 2H), 7.73 (m,J=7.60 Hz, 2H), 8.00 (dd, J=8.51, 2.52 Hz, 1H), 8.13 (dd, J=4.57, 1.42Hz, 1H), 8.27 (m, J=8.40, 2.70, 1.60 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H),8.85 (d, J=2.21 Hz, 1H), 9.45 (s, 1H). MS ES+m/z 333 [M+H]⁺.

Example 69:N-(furan-2-ylmethyl)-N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)benzamide

The title compound was prepared as described in Intermediate 53,starting from 4-[6-(3-pyridylamino)-3-pyridyl]benzoic acid and1-(2-furyl)-N-methyl-methanamine. Purification by preparative HPLC gavethe product as a solid (70 mg, 40%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.92 (s, 3H), 4.48 (br s, 1H), 4.68 (br s, 1H), 6.40 (br s, 1H),6.43-6.47 (m, 1H), 6.97 (d, J=8.51 Hz, 1H), 7.31 (dd, J=8.35, 4.57 Hz,1H), 7.53 (br s, 2H), 7.64-7.68 (m, 1H), 7.74 (br s, 1H), 7.75 (br s,1H), 8.00 (dd, J=8.67, 2.36 Hz, 1H), 8.12 (dd, J=4.57, 1.42 Hz, 1H),8.26 (m, J=8.30 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H), 8.84 (d, J=2.21 Hz,1H), 9.44 (s, 1H). MS ES+m/z 385 [M+H]⁺.

Example 70:N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)-N-(pyridin-3-ylmethyl)benzamide

The title compound was prepared as described in Intermediate 53,starting from 4-[6-(3-pyridylamino)-3-pyridyl]benzoic acid andN-methyl-1-(3-pyridyl)methanamine. Purification by preparative HPLC gavethe product as a solid (45 mg, 33%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm2.93 (s, 3H), 4.51-4.77 (m, 2H), 6.97 (br d, J=8.83 Hz, 1H), 7.31 (dd,J=8.20, 4.73 Hz, 1H), 7.42 (m, J=7.40, 4.90 Hz, 1H), 7.55 (br s, 2H),7.74 (m, J=7.90 Hz, 3H), 7.99 (br d, J=7.57 Hz, 1H), 8.12 (dd, J=4.41,1.26 Hz, 1H), 8.26 (m, J=8.50 Hz, 1H), 8.37-8.66 (m, 3H), 8.84 (d,J=2.21 Hz, 1H), 9.44 (s, 1H). MS ES+m/z 396 [M+H]⁺.

Example 71:N-methyl-4-(6-(pyridin-3-ylamino)pyridin-3-yl)-N-(thiazol-5-ylmethyl)benzamide

The title compound was prepared as described in Intermediate 53,starting from 4-[6-(3-pyridylamino)-3-pyridyl]benzoic acid andN-methyl-1-thiazol-5-yl-methanamine. Purification by preparative HPLCgave the product as a solid (48 mg, 27%). ¹H NMR (500 MHz, DMSO-d₆) δppm 2.94 (s, 3H), 4.85 (br s, 2H), 6.97 (dd, J=8.83, 0.63 Hz, 1H),7.29-7.32 (m, 1H), 7.51 (d, J=7.62 Hz, 2H), 7.75 (br d, J=8.20 Hz, 2H),7.90 (br s, 1H), 7.99 (dd, J=8.67, 2.68 Hz, 1H), 8.12 (dd, J=4.57, 1.42Hz, 1H), 8.26 (ddd, J=8.35, 2.68, 1.26 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H),8.84 (d, J=2.21 Hz, 1H), 9.07 (d, J=0.63 Hz, 1H), 9.46 (br s, 1H). MSES+m/z 402 [M+H]⁺.

Example 72:N,N-dimethyl-4-(6-((5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate56—1-(5-Bromo-3-pyridyl)-3-methyl-imidazolidin-2-one

60% NaH (62 mg, 1.61 mmol) was added to a suspension of1-(5-bromo-3-pyridyl)imidazolidin-2-one (300 mg, 1.24 mmol) in THF (5mL) at 0° C. The resulting mixture was stirred at rt for 1 h. MeI (85μL, 1.37 mmol) was added and the reaction mixture was stirred at rtovernight. More MeI (85 μL, 1.37 mmol) was added followed by DMF (1 mL)and the mixture was stirred for 2 h. Sat. aq. NH₄Cl (4 mL) was added andthe mixture extracted with EtOAc (3×5 mL). The combined organics werewashed with brine, dried over Na₂SO₄, filtered and concentrated to givethe product as a solid (280 mg, 89%). MS ES+m/z 256 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(3-methyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-methyl-imidazolidin-2-one and heating at 100° C.for 1 h, to give the product as a solid (20 mg, 12%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 2.79 (s, 3H), 2.94-3.12 (m, 6H), 3.41-3.58 (m, 2H),3.79-3.94 (m, 2H), 6.98 (d, 1H), 7.48 (d, 2H), 7.73 (d, 2H), 7.98 (dd,1H), 8.31 (br s, 1H), 8.42-8.49 (m, 1H), 8.54-8.60 (m, 1H), 8.67 (br s,1H), 9.42 (s, 1H). MS ES+m/z 417 [M+H]⁺.

Example 73:4-(6-((5-(3-benzyl-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-benzyl-3-(5-bromo-3-pyridyl)imidazolidin-2-one and heating at 90° C.for 6 h in toluene, to give the product as a solid (166 mg, 81%). ¹H NMR(500 MHz, METHANOL-d4) δ ppm 3.08 (s, 3H), 3.15 (s, 3H), 3.58 (dd,J=9.30, 7.09 Hz, 3H), 3.96-4.02 (m, 2H), 4.53-4.56 (m, 2H), 7.07-7.12(m, 1H), 7.37-7.41 (m, 5H), 7.56 (d, J=8.51 Hz, 2H), 7.73-7.78 (m, 3H),8.06-8.10 (m, 1H), 8.57-8.60 (m, 1H), 8.65-8.69 (m, 1H), 8.92-8.95 (m,1H), 9.36-9.40 (m, 1H). MS ES+m/z 493 [M+H]⁺.

Example 74:4-(6-((5-(3-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate57—1-(5-Bromo-3-pyridyl)-3-[(4-methoxyphenyl)methyl]imidazolidin-2-one

The title compound was prepared as described in Intermediate 56,starting from 1-(5-bromo-3-pyridyl)imidazolidin-2-one and1-(chloromethyl)-4-methoxy-benzene, replacing THF for DMF, to give theproduct as a solid (289 mg, quant.). MS ES+m/z 362 [M+H]⁺.

Step 2:4-(6-((5-(3-(4-methoxybenzyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-[(4-methoxyphenyl)methyl]imidazolidin-2-one andheating at 90° C. overnight, to give the product as a solid (250 mg,77%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br s, 6H), 3.34-3.42 (m,2H), 3.76 (s, 3H), 3.86 (br t, J=7.88 Hz, 2H), 4.36 (s, 2H), 6.93-7.01(m, 3H), 7.26 (d, J=8.51 Hz, 2H), 7.49 (d, J=8.20 Hz, 2H), 7.74 (d,J=8.20 Hz, 2H), 8.00 (dd, J=8.83, 2.52 Hz, 1H), 8.34 (d, J=2.21 Hz, 1H),8.47-8.49 (m, 1H), 8.58 (d, J=2.21 Hz, 1H), 8.71 (d, J=1.89 Hz, 1H),9.44 (s, 1H). MS ES+m/z 523 [M+H]⁺.

Example 75:N,N-dimethyl-4-(6-((5-(2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 55, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)imidazolidin-2-one, to give the product as a solid(15 mg, 9%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.99 (br s, 6H), 3.46 (t,J=7.88 Hz, 2H), 3.88-3.94 (m, 2H), 6.99 (d, J=8.83 Hz, 1H), 7.10 (s,1H), 7.49 (m, J=8.20 Hz, 2H), 7.73 (m, J=8.20 Hz, 2H), 7.99 (dd, J=8.83,2.52 Hz, 1H), 8.29 (d, J=2.21 Hz, 1H), 8.41 (t, J=2.21 Hz, 1H), 8.57 (d,J=2.52 Hz, 1H), 8.73 (d, J=2.21 Hz, 1H), 9.41 (s, 1H). MS ES+m/z 403[M+H]⁺.

Example 76:N,N-dimethyl-4-(6-((5-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate58—1-(5-Bromo-3-pyridyl)-3-(3-pyridylmethyl)imidazolidin-2-one

The title compound was prepared as described in Intermediate 56,starting from 1-(5-bromo-3-pyridyl)imidazolidin-2-one and3-(bromomethyl)pyridine HBr, replacing THF for DMF, to give the productas a solid (206 mg, quant.). MS ES+m/z 333 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-(3-pyridylmethyl)imidazolidin-2-one and heatingat 90° C. overnight, to give the product as a solid (46 mg, 15%). ¹H NMR(500 MHz, DMSO-d₆) δ ppm 2.99 (br s, 6H), 3.43-3.50 (m, 2H), 3.85-3.93(m, 2H), 4.47 (s, 2H), 6.99 (d, J=8.51 Hz, 1H), 7.42 (dd, J=7.72, 4.89Hz, 1H), 7.49 (d, J=8.20 Hz, 2H), 7.72-7.78 (m, 3H), 8.00 (dd, J=8.51,2.52 Hz, 1H), 8.34 (d, J=2.21 Hz, 1H), 8.49 (s, 1H), 8.53 (d, J=5.13 Hz,1H), 8.58 (s, 2H), 8.71 (d, J=2.21 Hz, 1H), 9.45 (s, 1H). MS ES+m/z 494[M+H]⁺.

Example 77:N,N-dimethyl-4-(6-((5-(2-oxo-3-((tetrahydrofuran-2-yl)methyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate59—1-(5-bromo-3-pyridyl)-3-(tetrahydrofuran-2-ylmethyl)imidazolidin-2-one

The title compound was prepared as described in Intermediate 56,starting from 1-(5-bromo-3-pyridyl)imidazolidin-2-one and2-(bromomethyl)tetrahydrofuran, replacing THF for DMF, to give theproduct as a solid (359 mg, 89%). MS ES+m/z 326 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(2-oxo-3-((tetrahydrofuran-2-yl)methyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-(tetrahydrofuran-2-ylmethyl)imidazolidin-2-oneand heating at 90° C. for 1.5 h, to give the product as a solid (31 mg,19%). ¹H NMR (500 MHz, CDCl₃) δ ppm 1.59-1.67 (m, 1H), 1.89-1.96 (m,2H), 1.99-2.08 (m, 1H), 3.01-3.18 (m, 6H), 3.25 (dd, J=14.50, 7.25 Hz,1H), 3.56 (dd, J=14.50, 3.15 Hz, 1H), 3.63-3.70 (m, 1H), 3.75-3.83 (m,2H), 3.87-3.93 (m, 3H), 4.10 (br dd, J=6.94, 2.84 Hz, 1H), 7.05 (br d,J=8.51 Hz, 1H), 7.51 (d, J=8.20 Hz, 2H), 7.58 (br d, J=8.20 Hz, 2H),7.80 (dd, J=8.51, 2.21 Hz, 1H), 8.34 (br s, 1H), 8.48-8.58 (m, 2H), 8.68(br s, 1H). MS ES+m/z 487 [M+H]⁺.

Example 78:N,N-dimethyl-4-(6-((5-(2-oxo-3-(thiazol-4-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate60—1-(5-Bromo-3-pyridyl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one

The title compound was prepared as described in Intermediate 56,starting from 1-(5-bromo-3-pyridyl)imidazolidin-2-one and4-(chloromethyl)thiazole HCl, replacing THF for DMF, to give the productas a solid (360 mg, 86%). MS ES+m/z 339 [M+H]⁺.

Step 2:N,N-dimethyl-4-(6-((5-(2-oxo-3-(thiazol-4-ylmethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-(tetrahydrofuran-2-ylmethyl)imidazolidin-2-oneand heating at 90° C. for 1.5 h, to give the product as a solid (16 mg,10%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.98 (br s, 6H), 3.52 (br t,J=8.04 Hz, 2H), 3.88 (br t, J=7.88 Hz, 2H), 4.57 (s, 2H), 6.98 (d,J=8.83 Hz, 1H), 7.48 (m, J=8.20 Hz, 2H), 7.63 (s, 1H), 7.73 (m, J=8.20Hz, 2H), 7.99 (dd, J=8.67, 2.36 Hz, 1H), 8.33 (d, J=2.21 Hz, 1H), 8.48(s, 1H), 8.57 (d, J=2.21 Hz, 1H), 8.68 (d, J=1.89 Hz, 1H), 9.11 (d,J=1.89 Hz, 1H), 9.43 (s, 1H). MS ES+m/z 500 [M+H]⁺.

Example 79:4-(6-((5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Intermediate61—1-(5-Bromo-3-pyridyl)-3-(cyclopropylmethyl)imidazolidin-2-one

The title compound was prepared as described in Intermediate 56,starting from 1-(5-bromo-3-pyridyl)imidazolidin-2-one and bromomethylcyclopropane, replacing THF for DMF, to give the product as a solid (308mg, 84%). MS ES+m/z 296 [M+H]⁺.

Step 2:4-(6-((5-(3-(cyclopropylmethyl)-2-oxoimidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-(tetrahydrofuran-2-ylmethyl)imidazolidin-2-oneand heating at 90° C. overnight, to give the product as a solid (4 mg,2%). ¹H NMR (500 MHz, CDCl₃) δ ppm 0.24-0.28 (m, 2H), 0.58 (dd, J=7.88,1.26 Hz, 2H), 0.91-1.03 (m, 1H), 3.01-3.17 (m, 6H), 3.20 (d, J=6.94 Hz,2H), 3.65-3.70 (m, 2H), 3.91 (dd, J=9.14, 6.94 Hz, 2H), 6.71 (s, 1H),6.99 (d, J=8.51 Hz, 1H), 7.49-7.53 (m, 2H), 7.56-7.60 (m, 2H), 7.80 (dd,J=8.67, 2.36 Hz, 1H), 8.21 (d, J=2.52 Hz, 1H), 8.41 (d, J=2.21 Hz, 1H),8.51 (d, J=1.89 Hz, 1H), 8.57 (t, J=2.36 Hz, 1H). MS ES+m/z 457 [M+H]⁺.

Example 80:(S)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate 62—1-[(1S)-1-phenylethyl]imidazolidin-2-one

2-Chloroethyl isocyanate (700 μL, 8.21 mmol) was added slowly to asolution of (1S)-1-phenylethanamine (1 mL, 7.82 mmol) in THF (5 mL) at0° C. and the resulting mixture was stirred at rt for 1 h. More2-chloroethyl isocyanate (250 μL, 2.93 mmol) was added and the mixturestirred at rt for 1 h. The mixture was cooled to 0° C. and KOtBu (1.32g, 11.7 mmol) was added slowly. The resulting mixture was stirred at rtfor 1 h and then extracted with EtOAc (3×10 mL). The combined organicswere washed with brine, dried over Na₂SO₄, filtered, concentrated andpurified on a silica gel column eluted with 0-100% EtOAc in heptane togive the product as an oil (780 mg, 52%). MS ES+m/z 191 [M+H]⁺.

Step 2: Intermediate63—1-(5-Bromo-3-pyridyl)-3-[(1S)-1-phenylethyl]imidazolidin-2-one

The title compound was prepared as described in Intermediate 14,starting from 3,5-dibromopyridine and1-[(1S)-1-phenylethyl]imidazolidin-2-one, to give the product as an oil(145 mg, 11%). MS ES+m/z 346 [M+H]⁺.

Step 3:(S)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-[(1S)-1-phenylethyl]imidazolidin-2-one andheating at 100° C. for 1 h, to give the product as a solid (15 mg, 8%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.54 (d, J=7.25 Hz, 3H), 2.98 (br s,6H), 3.11-3.20 (m, 1H), 3.56 (td, J=8.91, 6.78 Hz, 1H), 3.80-3.88 (m,2H), 5.18 (q, J=7.15 Hz, 1H), 6.98 (d, J=8.55 Hz, 1H), 7.26-7.32 (m,1H), 7.36-7.40 (m, 4H), 7.46-7.51 (m, 2H), 7.71-7.75 (m, 2H), 7.98 (dd,J=8.67, 2.68 Hz, 1H), 8.31 (d, J=2.21 Hz, 1H), 8.45 (t, J=2.36 Hz, 1H),8.57 (s, 1H), 8.70 (d, J=2.21 Hz, 1H), 9.43 (s, 1H). MS ES+m/z 507[M+H]⁺.

Example 81:(R)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Intermediate 64—1-[(1R)-1-phenylethyl]imidazolidin-2-one

The title compound was prepared as described in Intermediate 62,starting from (1R)-1-phenylethanamine, to give the product as an oil(365 mg, 25%). MS ES+m/z 191 [M+H]⁺.

Step 2: Intermediate65—1-(5-Bromo-3-pyridyl)-3-[(1R)-1-phenylethyl]imidazolidin-2-one

The title compound was prepared as described in Intermediate 14,starting from 3,5-dibromopyridine and1-[(1R)-1-phenylethyl]imidazolidin-2-one, to give the product as an oil(120 mg, 18%). MS ES+m/z 346 [M+H]⁺.

Step 3:(R)—N,N-dimethyl-4-(6-((5-(2-oxo-3-(1-phenylethyl)imidazolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

The title compound was prepared as described in Example 25, startingfrom 4-(6-amino-3-pyridyl)-N,N-dimethyl-benzamide and1-(5-bromo-3-pyridyl)-3-[(1R)-1-phenylethyl]imidazolidin-2-one andheating at 100° C. for 1 h, to give the product as a solid (35 mg, 21%).¹H NMR (500 MHz, DMSO-d₆) δ ppm 1.54 (d, J=7.25 Hz, 3H), 2.98 (br s,6H), 3.11-3.21 (m, 1H), 3.56 (td, J=8.91, 6.78 Hz, 1H), 3.80-3.89 (m,2H), 5.18 (q, J=7.15 Hz, 1H), 6.98 (d, J=8.58 Hz, 1H), 7.27-7.32 (m,1H), 7.36-7.40 (m, 4H), 7.45-7.51 (m, 2H), 7.71-7.75 (m, 2H), 7.98 (dd,J=8.67, 2.68 Hz, 1H), 8.31 (d, J=2.52 Hz, 1H), 8.45 (t, J=2.36 Hz, 1H),8.57 (s, 1H), 8.70 (d, J=2.21 Hz, 1H), 9.44 (s, 1H). MS ES+m/z 507[M+H]⁺.

Example 82:1-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Intermediate 66—1-[4-(6-Chloro-3-pyridyl)phenyl]pyrrolidin-2-one

The title compound was prepared as described in Intermediate 4, startingfrom 1-(4-bromophenyl)pyrrolidin-2-one and (6-chloro-3-pyridyl)boronicacid, and stirring the mixture at 75° C. for 3 h, to give the product asa solid (150 mg, 22%). MS ES+m/z 273 [M+H]⁺.

Step 2: 1-(4-(6-(pyridin-3-ylamino)pyridin-3-yl)phenyl)pyrrolidin-2-one

1-[4-(6-chloro-3-pyridyl)phenyl]pyrrolidin-2-one (75 mg, 0.27 mmol),pyridin-3-amine (40 mg, 0.43 mmol) and NaOtBu (60 mg, 0.62 mmol) weretaken up in 1,4-dioxane (5 mL) and the mixture was degassed withnitrogen for 5 min. Pd(OAc)₂ (5 mg, 0.02 mmol) and XPhos (25 mg, 0.05mmol) were added and the resulting mixture was stirred at 90° C.overnight. More pyridin-3-amine (40 mg, 0.43 mmol), NaOtBu (60 mg, 0.62mmol) and XPhos Pd G1 (10 mg, 0.01 mmol) were added and the mixturestirred at 100° C. overnight. pentanePPSI-Ipr (10 mg, 0.01 mmol) wasadded and stirring was continued at 90° C. overnight. When cooled to rtEtOAc (10 mL) and brine (10 mL) were added and the mixture filtered. Theorganic layer was separated and the aqueous layer extracted with EtOAc(2×5 mL). The combined organics were washed with brine, dried overNa₂SO₄, filtered, concentrated and purified by preparative HPLC to givethe product as a solid (15 mg, 17%). ¹H NMR (500 MHz, DMSO) δ=9.39 (s,1H), 8.83 (d, J=2.2 Hz, 1H), 8.56-8.51 (m, 1H), 8.30-8.23 (m, 1H), 8.10(d, J=4.4 Hz, 1H), 7.94 (dd, J=2.4, 8.7 Hz, 1H), 7.74 (d, J=8.8 Hz, 2H),7.67 (d, J=8.8 Hz, 2H), 7.30 (dd, J=4.6, 8.4 Hz, 1H), 6.95 (d, J=8.5 Hz,1H), 3.87 (t, J=7.1 Hz, 2H), 2.57-2.51 (m, 2H), 2.13-2.04 (m, 2H). MSES+m/z 331 [M+H]⁺.

Example 83:1-(4-(6-((6-methoxypyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 55, startingfrom 1-[4-(6-Chloro-3-pyridyl)phenyl]pyrrolidin-2-one and5-bromo-2-methoxy-pyridine, and replacing tBuOH for 1,4-dioxane andK₂CO₃ for Cs₂CO₃, to give the product as a solid (73 mg, 22%). 1H NMR(500 MHz, DMSO-d₆) δ ppm 2.09 (s, 2H) 2.52-2.55 (m, 2H) 3.80-3.85 (s,3H) 3.87 (t, J=7.09 Hz, 2H) 6.80 (d, J=8.74 Hz, 1H) 6.85 (d, J=8.51 Hz,1H) 7.65 (d, J=8.83 Hz, 2H) 7.73 (d, J=7.89 Hz, 2H) 7.86-7.91 (m, 1H)8.04-8.08 (m, 1H) 8.45 (dd, J=5.83, 2.36 Hz, 2H) 9.07 (s, 1H). MS ES+m/z361 [M+H]⁺.

Example 84:(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1 Intermediate67—(5S)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one

3-Bromo-2-chloro-5-nitro-pyridine (1 g, 4.21 mmol),(5S)-5-(hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) and K₂CO₃(700 mg, 5.06 mmol) were taken up in MeCN (10 mL) and the resultingmixture was stirred at 70° C. overnight. More(5S)-5-(hydroxymethyl)pyrrolidin-2-one (130 mg, 1.13 mmol) and K₂CO₃(300 mg, 2.17 mmol) were added and stirring continued at 70° C. for 5 h.When cooled to rt the mixture was diluted with water (10 mL) and EtOAc(10 mL) and the organic layer separated. The aqueous layer was extractedwith EtOAc (2×10 mL) and the combined organics were washed with brine,dried over Na₂SO₄, filtered and concentrated to give the product as asolid (1.13 g, 85%). MS ES+m/z 316 [M+H]⁺.

Step 2: Intermediate68—(6S)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1(9),10,12-trien-3-one

(5S)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one (1.13 g,3.57 mmol), CuI (75 mg, 0.39 mmol), N,N′-dimethylenediamine (85 μL, 0.8mmol) and K₂CO₃ (0.99 g, 7.15 mmol) were taken up in EtOAc (20 mL) andthe resulting mixture was stirred at 70° C. for 2 h. More CuI (75 mg,0.39 mmol) and N,N′-dimethylenediamine (85 μL, 0.8 mmol) were added andthe mixture was refluxed for 2 h. Cs₂CO₃ (2 g, 6.14 mmol) and1,4-dioxane (20 mL) were added and stirring continued at 100° C.overnight. When cooled to rt the mixture was filtered through celite andrinsed with EtOAc (2×5 mL). The filtrate was washed with half-saturatedbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give theproduct as a solid (720 mg, 86%). MS ES+m/z 236 [M+H]⁺.

Step 3: Intermediate69—(6S)-12-amino-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1 (9),10,12-trien-3-one

(6S)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1 (9),10,12-trien-3-one (357 mg, 1.52 mmol), Fe (509mg, 9.11 mmol) and ammonium chloride (244 mg, 4.55 mmol) were taken upin EtOH/H₂O (4:1, 12.5 mL) and the resulting mixture was refluxed for1.5 h. When cooled to rt the mixture was filtered through celite, rinsedwith MeOH and the filtrate was concentrated. The resulting residue wassuspended in water and pH was adjusted to ˜7 by careful addition of asat. aq. NaHCO₃. The mixture was extracted with EtOAc and the combinedorganics were dried over Na₂SO₄, filtered and concentrated to give theproduct as a solid (212 mg, 68%). MS ES+m/z 206 [M+H]⁺.

Step 4:(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

The title compound was prepared as described in Example 59, startingfrom 1-[4-(6-Chloro-3-pyridyl)phenyl]pyrrolidin-2-one and(6S)-12-amino-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1 (9),10,12-trien-3-one, and stirring at 90° C.overnight, to give the product as a solid (6 mg, 4%). ¹H NMR (500 MHz,DMSO-d₆) δ ppm 1.63-1.77 (m, 1H), 2.05-2.12 (m, 2H), 2.17-2.27 (m, 1H),2.34-2.44 (m, 1H), 2.51-2.58 (m, 2H), 2.67 (ddd, J=16.87, 11.19, 9.46Hz, 1H), 3.84-3.94 (m, 3H), 4.07 (tdd, J=9.65, 9.65, 6.86, 3.15 Hz, 1H),4.58 (dd, J=10.88, 2.99 Hz, 1H), 6.88 (d, J=8.51 Hz, 1H), 7.65 (d,J=7.82 Hz, 2H), 7.72 (d, J=8.55 Hz, 2H), 7.89 (dd, J=8.83, 2.52 Hz, 1H),8.45 (dd, J=5.83, 2.36 Hz, 2H), 8.97 (d, J=2.52 Hz, 1H), 9.21 (s, 1H).MS ES+m/z 442 [M+H]⁺.

Example 85:(R)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Intermediate70—(5R)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one

The title compound was prepared as described in Intermediate 67,starting from 3-bromo-2-chloro-5-nitro-pyridine and(5R)-5-(hydroxymethyl)pyrrolidin-2-one, to give the product as a solid(1.46 g, 73%). MS ES+m/z 316 [M+H]⁺.

Step 2: Intermediate 71—:(6R)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1(9),10,12-trien-3-one

The title compound was prepared as described in Intermediate 68,starting from(5R)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one, to givethe product as a solid (609 mg, 56%). MS ES+m/z 236 [M+H]⁺.

Step 3: Intermediate72—(R)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

(6R)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.0{circumflex over( )}{2,6}]trideca-1(9),10,12-trien-3-one (254 mg, 1.08 mmol) wassuspended in MeOH (40 mL). Sodium dithionite (752 mg, 4.32 mmol) inwater (2 mL) was added and the reaction mixture was stirred at 50° C.for 1 h. When cooled to rt conc. HCl (2 mL) was added and the mixturewas stirred at 50° C. for 2 h. The mixture was concentrated and to theresulting residue was added saturated NaHCO₃. The mixture was extractedwith DCM and the combined organics were dried over MgSO₄, filtered andconcentrated to give the product as a solid (63 mg, 28%). MS ES+m/z 206[M+H]⁺.

Step 4:(R)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

The title compound was prepared as described in Example 55, startingfrom 1-[4-(6-amino-3-pyridyl)phenyl]pyrrolidin-2-one and(R)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,replacing K₂CO₃ with Cs₂CO₃ and tBuOH with 1,4-dioxane, to give theproduct as a solid (56 mg, 58%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm1.68-1.75 (m, 1H), 2.06-2.12 (m, 2H), 2.24 (s, 1H), 2.40 (s, 1H),2.61-2.78 (m, 2H),3.84-3.98 (m, 3H), 4.00-4.17 (m, 1H), 4.59 (dd,J=11.03, 3.15 Hz, 1H), 6.87-6.90 (m, 1H), 7.65-7.69 (m, 2H), 7.72-7.82(m, 2H), 7.90 (dd, J=8.67, 2.68 Hz, 1H), 8.45-8.48 (m, 2H), 8.97 (d,J=2.52 Hz, 1H), 9.22 (s, 1H). MS ES+m/z 442 [M+H]⁺.

Example 86:1-(4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Intermediate 73—1-[4-(6-Amino-3-pyridyl)phenyl]pyrrolidin-2-one

The title compound was prepared as described in Intermediate 3, startingfrom 1-(4-bromophenyl)pyrrolidin-2-one and5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine andstirring the mixture at 75° C. for 3 h, to give the product as a solid(150 mg, 14%). MS ES+m/z 254 [M+H]⁺.

Step 2:1-(4-(6-((1-acetyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 55, startingfrom 1-[4-(6-amino-3-pyridyl)phenyl]pyrrolidin-2-one and1-(7-bromo-2,3-dihydropyrido[2,3-b][1,4]oxazin-1-yl)ethanone, replacingK₂CO₃ with Cs₂CO₃ and tBuOH with 1,4-dioxane, to give the product as asolid (29 mg, 18%). ¹H NMR (500 MHz, DMSO-d₆) δ ppm 2.09 (quin, J=7.57Hz, 2H), 2.31 (s, 3H), 2.53-2.59 (m, 1H), 3.83-3.92 (m, 4H), 4.32-4.38(m, 2H), 6.87 (d, J=8.51 Hz, 1H), 7.66 (d, J=8.83 Hz, 2H), 7.71-7.75 (m,2H), 7.90 (dd, J=8.83, 2.52 Hz, 1H), 8.32 (br s, 1H), 8.46 (d, J=2.52Hz, 1H), 9.15 (s, 1H). MS ES+m/z 430 [M+H]⁺.

Example 87:1-(4-(6-((2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

The title compound was prepared as described in Example 25, startingfrom 1-[4-(6-Amino-3-pyridyl)phenyl]pyrrolidin-2-one and7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine and stirring the mixtureat 80° C. for 2 days, to give the product as a solid (20 mg, 16%). ¹HNMR (500 MHz, METHANOL-d4) δ ppm 2.21 (t, J=7.57 Hz, 2H), 2.62 (t,J=8.20 Hz, 2H), 3.97 (t, J=7.09 Hz, 2H), 4.27-4.30 (m, 2H), 4.41 (dt,J=4.02, 2.25 Hz, 2H), 6.84 (dd, J=8.83, 0.63 Hz, 1H), 7.60-7.64 (m, 2H),7.69 (d, J=7.86 Hz, 2H), 7.80 (d, J=2.21 Hz, 1H), 7.85 (dd, J=8.51, 2.52Hz, 1H), 7.90 (d, J=2.21 Hz, 1H), 8.39 (dd, J=2.52, 0.63 Hz, 1H). MSES+m/z 389 [M+H]⁺.

Example 88:N,N-dimethyl-4-(6-((2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

Step 1 Preparation of ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate

To a mixture of ethyl 2-hydroxyacetate (14.0 g, 134 mmol) in anhydrousTHF (150 mL) was added NaH (4.48 g, 112 mmol, 60% in mineral oil) at 0°C. After stirring for 30 min, 5-bromo-2-chloro-3-nitropyridine (26.6 g,112 mmol) was added at 0° C., and the reaction mixture was stirred at25° C. for 15.5 h. TLC showed the reaction was almost completed. Thecolour of mixture was black. The residue was poured into water (150 mL)at 0° C. and extracted with EtOAc (100 mL×3). The combined organic phasewas dried over anhydrous Na₂SO₄, filtered and concentrated in vacuum.The residue was purified by Combi Flash (6% EtOAc in pentane) to giveethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (16.5 g, yield: 48%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 1.26 (3H, t, J=7.2 Hz),4.23 (2H, q, J=7.2 Hz), 5.04 (2H, s), 8.39 (1H, d, J=2.4 Hz), 8.46 (1H,d, J=2.4 Hz).

Step 2: Preparation of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a mixture of ethyl 2-((5-bromo-3-nitropyridin-2-yl)oxy)acetate (17.5g, 57.3 mmol) in anhydrous acetic acid (150 mL) was added Fe (48.9 g,832 mmol) at 25° C. After stirring for 3 h at 60° C., the colour of themixture was from yellow to black. TLC showed the reaction was almostcompleted. Acetic acid was removed under reduced pressure; the residuewas diluted with DMF (500 mL), filtered and concentrated under reducedpressure. The residue was washed with EtOAc (20 mL) to give7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (26.7 g, crude) as abrick-red solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.82 (2H, s), 7.34 (1H, s),7.89 (1H, s), 10.96 (1H, s).

Step 3: Preparation of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine

To a solution of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (26.7 g,crude) in THF (100 mL) was added BH₃-THF (1 M in THF, 349 mL) at 0° C.The ice bath was removed and the solution was heated at 70° C. for 3 h.The colour of mixture was from red to black. TLC showed the reaction wasalmost completed. MeOH (120 mL) was added at 0° C., filtered andconcentrated. The reaction mixture was purified by Combi Flash (50%EtOAc in pentane) to give7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (4.40 g, yield: 18% viatwo steps) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.40-3.43 (2H,m), 3.97 (1H, br s), 4.38-4.40 (2H, m), 6.69 (1H, d, J=2.4 Hz), 7.62(1H, d, J=2.4 Hz).

Step 4: Preparation of 4-bromo-N,N-dimethylbenzamide

A mixture of 4-bromobenzoic acid (21.0 g, 105 mmol) in SOCl₂ (35 mL) washeated at 80° C. for 2 h under N₂ atmosphere. After cooling, thereaction mixture was concentrated under reduced pressure. Then to themixture was added DCM (100 mL), Me₂NH (11.1 g, 136 mmol) and TEA (87mL), and stirred at 25° C. for 16 h under N₂. TLC showed the reactionwas completed. The residue was poured into water (50 mL) and extractedwith DCM (50 mL×3). The combined organic layer was washed with water(100 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuum. The residue was purified by Combi Flash (10% EtOAc in pentane)to afford 4-bromo-N,N-dimethylbenzamide (23.7 g, yield: 99%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.89 (3H, s), 2.97 (3H, s), 7.36 (2H,d, J=8.8 Hz), 7.63 (2H, d, J=8.4 Hz).

Step 5: Preparation ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

A mixture of 4-bromo-N,N-dimethylbenzamide (23.0 g, 100 mmol), B₂Pin₂(38.4 g, 151 mmol), KOAc (29.7 g, 303 mmol) and Pd(dppf)Cl₂ (2.95 g,4.03 mmol) in dioxane (100 mL) was stirred at 110° C. for 5 h under N₂atmosphere. The red suspension turned to black. Crude LCMS (Rt=0.679min; MS Calc'd: 275.1; MS Found: 275.8 [M+H]⁺). The reaction mixture wasdiluted with EtOAc (200 mL), filtered and concentrated to give crudeN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(35.0 g, crude) as black oil and directly used to next step.

Step 6: Preparation of 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide

A mixture ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(12.0 g, 43.6 mmol), 5-bromopyridin-2-amine (6.86 g, 39.7 mmol), Na₂CO₃(16.5 g, 198 mmol) in water (30 mL) and Pd(dppf)Cl₂ (2.90 g, 3.96 mmol)in DME (100 mL) was stirred at 110° C. for 16 h under N₂ atmosphere.Crude LCMS (Rt=0.507 min; MS Calc'd: 241.1; MS Found: 242.1 [M+H]⁺). Thereaction mixture was diluted with ethyl acetate (50 mL), dried overNa₂SO₄, filtered and concentrated. The residue was purified by CombiFlash (EtOAc) to afford 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide(5.2 g, yield: 54% for two steps) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.97 (6H, s), 6.14 (2H, br s), 6.53 (1H, d, J=8.8 Hz), 7.43(2H, dd, J=6.8, 2.0 Hz), 7.62 (2H, dd, J=6.4, 1.6 Hz), 7.74 (1H, dd,J=8.4, 2.4 Hz), 8.29 (1H, d, J=2.4 Hz).

Step 7: Preparation of7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one

To a solution of 7-bromo-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one (500 mg,2.18 mmol) was added NaH (130 mg, 3.27 mmol, 60% in mineral oil) in DMF(10 mL). The reaction mixture was cooled to 0° C. for 0.5 hour, andSEMCl (726 mg, 4.36 mmol) was added dropwise. The reaction mixture waswarmed to 20° C., stirred at 20° C. for 20 h under N₂ atmosphere. Thecolorless solution turned to dark red gradually. LCMS (Rt=0.899 min; MSCalc'd: 358.0; MS Found: 358.9 [M+H]⁺). The reaction mixture wasquenched with MeOH (1 mL), then DMF was removed under reduced pressure.The residue was purified by Combi Flash (70% DCM in pentane) to afford7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(383 mg, yield: 49%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 0.003(9H, s), 0.95 (2H, t, J=8.0 Hz), 3.64 (2H, t, J=8.0 Hz), 4.83 (2H, s),5.29 (2H, s), 7.73 (1H, d, J=2.0 Hz), 8.01 (1H, d, J=2.0 Hz).

Step 8: Preparation ofN,N-dimethyl-4-(6-((2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

A mixture of Pd₂(dba)₃ (35 mg, 0.039 mmol) and Brettphos (42 mg, 0.078mmol) in dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-Aminopyridin-3-yl)-N,N-dimethylbenzamide (188 mg, 0.779 mmol),7-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrido[2,3-b][1,4]oxazin-2(3H)-one(280 mg, 0.779 mmol) in dioxane (16 mL) and Cs₂CO₃ (508 mg, 1.56 mmol)were added. The resulting mixture was stirred at 100° C. for 14 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.658 min; MS Calc'd: 519.2; MS Found: 519.8 [M+H]⁺). Thereaction mixture was diluted with DCM (20 mL), filtered andconcentrated. The residue was purified by Combi Flash (EtOAc) to giveN,N-dimethyl-4-(6-((2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide(450 mg, yield: 82%) as alight yellow solid. ¹H NMR (400 MHz, CDCl₃) δ0.007 (9H, s), 0.96 (2H, t, J=8.4 Hz), 3.04 (3H, s), 3.14 (3H, s), 3.66(2H, t, J=8.4 Hz), 4.82 (2H, s), 5.35 (2H, s), 6.56 (1H, br s), 7.78(1H, d, J=8.8 Hz), 7.47-7.57 (4H, m), 7.74 (1H, dd, J=8.8, 2.4 Hz), 7.97(1H, d, J=2.0 Hz), 8.01 (1H, d, J=2.4 Hz), 8.45 (1H, d, J=2.4 Hz).

Step 9: Preparation ofN,N-dimethyl-4-(6-((2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

To a solution ofN,N-dimethyl-4-(6-((2-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide(100 mg, 0.192 mmol) in DCM (3 mL) was added TFA (3 mL, 40.5 mmol) at10° C., and it was stirred at 10° C. for 1 hour. Then the mixture wasconcentrated under reduced pressure and the residue was diluted withMeOH (3 mL) and then EDA (439 mg, 3.85 mmol) was added at 10° C. Theresidue was stirred at 10° C. for 16 h. The yellow solution turned tosuspension gradually. Crude LCMS showed the purity of product (Rt=0.501min, MS Calc'd: 389.2; MS Found: 389.7 [M+H]⁺). The mixture wasconcentrated under reduced pressure. The residue was purified byprep-HPLC (0.1% NH₃.H₂O as an additive) and lyophilized to giveN,N-dimethyl-4-(6-((2-oxo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide(32.9 mg, yield: 44%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 100%, Rt=2.190 min; MSCalc'd.: 389.2, MS Found: 390.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.97(6H, s), 4.70 (2H, s), 6.08 (1H, br s), 6.90 (1H, d, J=9.2 Hz), 7.47(2H, d, J=7.2 Hz), 7.70 (2H, d, J=7.2 Hz), 7.80 (1H, s), 7.95 (1H, d,J=8.8 Hz), 8.08 (1H, s), 8.50 (1H, s), 9.32 (1H, br s).

Example 89:4-(6-((1-(2-hydroxyacetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of2-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate

A solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (200 mg,0.930 mmol) in THF (2 mL) was added EtOAc (282 mg, 2.79 mmol) and2-chloro-2-oxoethyl acetate (508 mg, 3.72 mmol) at 0° C. The ice bathwas removed and the mixture was stirred for 2 h at 25° C. The greensolution turned to suspension. TLC showed the reaction was completed.The mixture was concentrated under reduced pressure. The residue waspurified by Combi Flash (1% MeOH in DCM) to give2-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate (320 mg, crude) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.05 (3H, s), 3.86 (2H, t, J=4.8 Hz), 4.40 (2H, t, J=4.8 Hz), 5.01 (2H,s), 8.05 (1H, d, J=2.4 Hz), 8.67 (1H, s).

Step 2: Preparation of2-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate

A solution of Pd₂(dba)₃ (85 mg, 0.093 mmol) and Brettphos (100 mg, 0.186mmol) in dioxane (6 mL) was stirred at 50° C. for 10 min.2-(7-Bromo-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate (293 mg, 0.930 mmol),4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (224 mg, 0.930 mmol),dioxane (6 mL) and Cs₂CO₃ (606 mg, 1.86 mmol) were added, and theresulting mixture was stirred at 100° C. for 12 h. The red solutionturned to dark red. Crude LCMS (Rt=0.623 min; MS Calc'd: 475.2; MSFound: 476.2 [M+H]⁺). Concentrated in vacuum. The residue was purifiedby Combi Flash (34% EtOAc in DCM) to give2-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate (234 mg, yield: 53%) as alight yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.12 (3H, s), 2.97 (6H, s), 3.85 (2H, t, J=4.0 Hz), 4.35 (2H,t, J=4.0 Hz), 5.03 (2H, s), 6.87 (1H, d, J=9.2 Hz), 7.47 (2H, dd, J=6.4,1.6 Hz), 7.71 (2H, dd, J=6.4, 1.6 Hz), 7.94 (1H, dd, J=8.8, 2.4 Hz),8.43 (1H, s), 8.50 (1H, d, J=2.0 Hz), 8.72 (1H, br s), 9.24 (1H, s).

Step 3: Preparation of4-(6-((1-(2-hydroxyacetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a solution of2-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-oxoethylacetate (80 mg, 0.017 mmol) in dioxane (4 mL) was added MeOH (1.6 mL,39.4 mmol). Then the colorless solution was added K₂CO₃ (70 mg, 0.050mmol), stirred at 20° C. for 2 h. LCMS (Rt=0.582 min; MS Calc'd: 433.2;MS Found: 434.2 [M+H]⁺). The reaction mixture was concentrated. Theresidue was purified by prep-HPLC (0.05% NH₃.H₂O as an additive) andlyophilized to afford4-(6-((1-(2-hydroxyacetyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(30 mg, yield: 41%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 96.39%, Rt=2.208 min; MSCalc'd.: 433.2, MS Found: 434.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.99(6H, s), 3.83 (2H, t, J=3.6 Hz), 4.30-4.41 (4H, m), 5.08 (1H, t, J=6.0Hz), 6.90 (1H, d, J=8.8 Hz), 7.48 (2H, d, J=8.0 Hz), 7.71 (2H, d, J=8.0Hz), 7.95 (1H, dd, J=8.0, 2.0 Hz), 8.34 (1H, d, J=2.4 Hz), 8.51 (1H, d,J=2.0 Hz), 8.81 (1H, br s), 9.25 (1H, s).

Example 90:4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(cyclopropyl)methanone

In a separate vial, to a solution of cyclopropanecarboxylic acid (240mg, 2.79 mmol) in DCM (2 mL), DMF (25 mg, 0.349 mmol) was added oxalylchloride (0.3 mL, 3.49 mmol). The reaction mixture was stirred at 20° C.for 0.5 hour. A light yellow solution was formed. The mixture wasconcentrated to give crude cyclopropanecarbonyl chloride as a yellowoil. To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazinein DCM (6 mL) was added TEA (0.5 mL, 3.49 mmol). The reaction mixturewas cooled to 0° C. and then added cyclopropanecarbonyl chloride in DCM(2 mL) dropwise. The reaction mixture was then warmed to 20° C., stirredat 20° C. for 2 h under N₂ atmosphere. The colorless solution turned toyellow gradually. LCMS showed the purity of the desired product(Rt=0.601 min; MS Calc'd: 282.0; MS Found: 282.6 [M+H]⁺). The reactionmixture was concentrated together with the last reaction (es6012-100).The residue was purified by Combi Flash (1% TEA in DCM) to afford(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(cyclopropyl)methanone(240 mg, yield: 92%) as a yellow gum. ¹H NMR (400 MHz, CDCl₃) δ0.95-1.01 (2H, m), 1.17-1.23 (2H, m), 1.89-1.20 (1H, m), 4.02 (2H, t,J=4.8 Hz), 4.46 (2H, t, J=4.8 Hz), 8.06 (1H, d, J=2.4 Hz), 8.20 (1H, brs).

Step 2: Preparation of4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of Pd₂(dba)₃ (19 mg, 0.021 mmol) and Brettphos (23 mg, 0.042mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-Aminopyridin-3-yl)-N,N-dimethylbenzamide (102 mg, 0.424 mmol),(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(cyclopropyl)methanone(120 mg, 0.424 mmol) in dioxane (8 mL) and Cs₂CO₃ (276 mg, 0.848 mmol)were added, and the resulting mixture was stirred at 100° C. for 6 h. Ablack brown mixture was formed. LCMS (Rt=0.542 min; MS Calc'd: 443.2; MSFound: 443.8 [M+H]⁺). The reaction mixture was filtered. The mixture waspurified by prep-HPLC (normal phase, Hexane-EtOH (5-70% B)) andlyophilized to give impure product (85 mg) as an off-white solid, thenpurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized togive4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(65.2 mg, yield: 35%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is95.84%, Rt=1.193 min; MS Calc'd.: 443.2; MS Found: 444.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 0.85-1.06 (4H, m), 2.12-2.29 (1H, m), 2.98 (6H, s),3.94-4.02 (2H, m), 4.37 (2H, t, J=4.4 Hz), 6.88 (1H, d, J=8.8 Hz), 7.47(2H, d, J=8.0 Hz), 7.70 (2H, d, J=8.4 Hz), 7.93 (1H, dd, J=8.8, 2.4 Hz),8.21 (1H, br s), 8.47 (1H, d, J=2.4 Hz), 8.67 (1H, d, J=2.4 Hz), 9.27(1H, br s).

Example91:1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate

Step 1: Preparation of 2-acetoxypropanoic acid

2-Hydroxypropanoic acid (900 mg, 9.99 mmol) was slowly added acetylchloride (1.4 mL, 20.0 mmol) at 0° C. Then the reaction mixture waswarmed to 20° C., stirred at 20° C. for 16 h under N₂ atmosphere. Ayellow solution was formed gradually. TLC showed the reaction wascompleted nearly. Acetyl chloride was removed under reduced pressure toafford 2-acetoxypropanoic acid (1.20 g, yield: 90%) as yellow oil. ¹HNMR (400 MHz, CDCl₃) δ 1.53 (3H, d, J=7.2 Hz), 2.14 (3H, s), 5.11 (1H,q, J=7.2 Hz).

Step 2: Preparation of1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate

In a separate vial, to a solution of 2-acetoxypropanoic acid (245 mg,1.86 mmol) in DCM (2 mL), DMF (17 mg, 0.23 mmol) was added oxalylchloride (0.2 mL, 2.33 mmol). The reaction mixture was stirred at 20° C.for 0.5 hour. A light yellow solution was formed. The mixture wasconcentrated to give yellow oil. To a solution of7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (100 mg, 0.465 mmol) inDCM (5 mL) was added TEA (0.3 mL, 2.33 mmol). The reaction mixture wascooled to 0° C. and then added 1-chloro-1-oxopropan-2-yl acetate in DCM(2 mL) dropwise. The reaction mixture was then warmed to 20° C., stirredat 20° C. for 2 h under N₂ atmosphere. The colorless solution turned todark red gradually. LCMS showed the purity of the desired product(Rt=0.583 min; MS Calc'd: 328.0; MS Found: 329.3 [M+H]⁺). The reactionmixture was concentrated. The residue was purified by Combi Flash (1%TEA in DCM) to afford1-(7-bromo-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate (180 mg, yield: 94%). ¹H NMR (400 MHz, CDCl₃) δ 1.51 (3H, d,J=6.4 Hz), 2.13 (3H, s), 3.73-3.84 (1H, m), 4.00-4.10 (1H, m), 4.40-4.52(2H, m), 5.43 (1H, q, J=6.8 Hz), 8.08 (1H, d, J=2.0 Hz), 8.45 (1H, brs).

Step 3: Preparation of1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate

A mixture of Pd₂(dba)₃ (20 mg, 0.022 mmol) and Brettphos (23 mg, 0.044mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (105 mg, 0.437 mmol),1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate (180 mg, 0.437 mmol) in dioxane (8 mL) and Cs₂CO₃ (285 mg, 0.875mmol) were added, and the resulting mixture was stirred at 100° C. for 6h. A black brown mixture was formed. LCMS showed the purity of thedesired product (Rt=0.642 min; MS Calc'd: 489.2; MS Found: 490.3[M+H]⁺). The reaction mixture was diluted with dioxane (10 mL), filteredand concentrated. The residue was purified by Combi Flash (40% EtOAc inDCM (1% TEA as an additive)) to give1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate (75 mg) as an off-white solid. The impure product (15 mg) waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized togive1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate (2.61 mg) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 99.32%, Rt=2.603 min; MSCalc'd.: 489.2, MS Found: 490.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.57(3H, d, J=6.8 Hz), 2.12 (3H, s), 3.04 (3H, s), 3.13 (3H, s), 3.85-4.09(2H, m), 4.39-4.58 (2H, m), 5.50-5.68 (1H, m), 6.42 (1H, s), 6.79 (1H,d, J=8.0 Hz), 7.50 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz), 7.75 (1H,dd, J=8.4, 2.4 Hz), 8.06 (1H, s), 8.42 (1H, d, J=2.0 Hz), 8.52 (1H, brs).

Example 92:4-(6-((1-(2-hydroxypropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a solution of1-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-1-yl)-1-oxopropan-2-ylacetate (60 mg, 0.12 mmol) in dioxane (4 mL) was added MeOH (0.5 mL).Then the red solution was added K₂CO₃ (51 mg, 0.37 mmol), stirred at 20°C. for 2 h. The mixture was added MeOH (0.5 mL), stirred at 20° C. foranother 2 h. LCMS (Rt=0.614 min; MS Calc'd: 447.2; MS Found: 448.3[M+H]⁺). The reaction mixture was concentrated. The residue was purifiedby prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to afford4-(6-((1-(2-hydroxypropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(9.4 mg, yield: 17%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 96.79%, Rt=2.309 min; MSCalc'd.: 447.2, MS Found: 448.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.44(3H, d, J=6.4 Hz), 3.04 (3H, s), 3.14 (3H, s), 3.58 (1H, br s),3.73-4.18 (2H, m), 4.34-4.57 (2H, m), 4.61-4.88 (1H, m), 6.52 (1H, s),6.81 (1H, d, J=8.0 Hz), 7.50 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=7.6 Hz),7.77 (1H, dd, J=8.4, 2.4 Hz), 8.08 (1H, s), 8.45 (1H, d, J=2.4 Hz), 8.68(1H, br s).

Example 93: methyl7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

Step 1: Preparation of methyl7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

To a solution of 7-bromo-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazine (100mg, 0.465 mmol) in DCM (5 mL) was added TEA (212 mg, 2.09 mmol). Thereaction mixture was cooled to 0° C. and then added methylcarbonochloridate (1.31 g, 13.86 mmol) dropwise. The reaction mixturewas then warmed to 20° C., stirred at 20° C. for 18 h under N₂atmosphere. The colorless solution turned to yellow gradually. LCMSshowed the purity of the desired product is 33% (Rt=0.692 min; MSCalc'd: 272.0; MS Found: 272.9 [M+H]⁺). The reaction mixture wasconcentrated. The residue was purified by Combi Flash (50% DCM inpentane (1% TEA as an additive)) to afford methyl7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (65 mg,yield: 51%) as a yellow gum.

¹H NMR (400 MHz, CDCl₃) δ 3.87 (3H, s), 3.93 (2H, t, J=4.4 Hz), 4.39(2H, t, J=4.8 Hz), 7.99 (1H, d, J=2.4 Hz), 8.52 (1H, br s).

Step 2: Preparation of methyl7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

A mixture of Pd₂(dba)₃ (11 mg, 0.012 mmol) and Brettphos (13 mg, 0.024mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (57 mg, 0.24 mmol), methyl7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate (65 mg,0.238 mmol) in dioxane (3 mL) and Cs₂CO₃ (155 mg, 0.476 mmol) wereadded, and the resulting mixture was stirred at 100° C. for 6 h. A blackbrown mixture was formed. LCMS (Rt=0.648 min; MS Calc'd: 433.2; MSFound: 434.2 [M+H]⁺). The reaction mixture was filtered. The mixture waspurified by prep-HPLC (normal phase, hexane-IPA (15-100% B)) andlyophilized to give methyl7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(8.1 mg, yield: 8%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is98.90%, Rt=1.156 min; MS Calc'd.: 433.2; MS Found: 434.0 [M+H]⁺. ¹H NMR(400 MHz, CDCl₃) δ 3.04 (3H, s), 3.13 (3H, s), 3.86 (3H, s), 3.96 (2H,t, J=4.8 Hz), 4.41 (2H, t, J=4.8 Hz), 6.52 (1H, br s), 6.81 (1H, d,J=8.8 Hz), 7.49 (2H, d, J=8.0 Hz), 7.56 (2H, d, J=8.0 Hz), 7.75 (1H, dd,J=8.4, 2.4 Hz), 8.01 (1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.0 Hz), 8.54(1H, br s).

Example 94:4-(6-((1-benzoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(phenyl)methanone

To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (500mg, 2.33 mmol) in DCM (5 mL) was added TEA (1 mL, 7 mmol) and benzoylchloride (983 mg, 6.99 mmol) at 0° C., the mixture was stirred at 25° C.for 2 h. TLC showed the starting material was consumed completely. Thesolution was yellow. The reaction mixture was concentrated and purifiedby Combi Flash (50% EtOAc in pentane) to give(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(phenyl)methanone(500 mg, yield: 67%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.94(2H, t, J=4.8 Hz), 4.30 (2H, t, J=4.8 Hz), 7.40-7.60 (5H, m), 7.90-8.15(2H, m).

Step 2: Preparation of4-(6-((1-benzoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(phenyl)methanone(100 mg, 0.313 mmol), 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (76mg, 0.31 mmol), Pd₂(dba)₃ (14 mg, 0.016 mmol), Brettphos (17 mg, 0.031mmol) and Cs₂CO₃ (306 mg, 0.940 mmol) in dioxane (3 mL) was stirred at100° C. for 16 h. LCMS (Rt=0.694 min; MS Calc'd: 479.2; MS Found: 480.1[M+H]⁺). A black suspension was formed. The mixture was filtered andconcentrated to give an orange gum. The residue was purified byprep-HPLC (Welch diol; DCM-MeCN) to give4-(6-((1-benzoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(28.0 mg, yield: 19%) as a white solid.

LCMS (Shimadzu LCMS 2010, Mobile phase: from 90% [water+0.04% TFA] and10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA]in 1.35 min, then under this condition for 0.9 min, finally changed to90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] and under this conditionfor 0.75 min.) purity is 98.94%, Rt=1.337 min; MS Calc'd.: 479.2; MSFound: 480.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 2.98 (6H, s), 3.87 (2H,t, J=4.8 Hz), 4.38 (2H, t, J=4.4 Hz), 6.76 (1H, d, J=8.8 Hz), 7.40-7.55(5H, m), 7.60 (2H, d, J=2.4 Hz), 7.90 (2H, d, J=8.4 Hz), 7.89 (1H, d,J=8.8 Hz), 8.25 (1H, s), 8.41 (2H, d, J=2.4 Hz), 9.17 (1H, br s).

Example 95:N,N-dimethyl-4-(6-((1-picolinoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

Step 1: Preparation of(7-bromo-2,3-dihydro-H-pyrido[2,3-b][1,4]oxazin-1-yl)(pyridin-2-yl)methanone

To a mixture of picolinic acid (172 mg, 1.40 mmol) in SOCl₂ (3 mL) wasstirred at 80° C. for 2 h. The orange solution turned to blue gradually.SOCl₂ was removed under reduced pressure to give crude picolinoylchloride as a green solid. To a solution of7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (100 mg, 0.465 mmol) inTHF (3 mL) was added TEA (235 mg, 2.33 mmol). The reaction mixture wascooled to 0° C. and then added picolinoyl chloride in THF (1 mL)dropwise. The reaction mixture was then warmed to 20° C., stirred at 20°C. for 2 h under N₂ atmosphere. The blue mixture turned to browngradually. LCMS is 94% (Rt=0.681 min; MS Calc'd: 319.0; MS Found: 319.9[M+H]⁺). The mixture was concentrated. The residue was purified by CombiFlash (1% TEA in DCM) to give(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(pyridin-2-yl)methanone(160 mg, yield: 98%) as a red gum. ¹H NMR (400 MHz, CDCl₃) δ 4.09 (2H,t, J=4.8 Hz), 4.47 (2H, t, J=4.8 Hz), 7.42-7.47 (1H, m), 7.84 (1H, d,J=8.0 Hz), 7.86-7.93 (1H, m), 8.06 (1H, d, J=2.0 Hz), 8.37 (1H, br s),8.62 (1H, d, J=4.4 Hz).

Step 2: Preparation ofN,N-dimethyl-4-(6-((1-picolinoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

A mixture of Pd₂(dba)₃ (11 mg, 0.012 mmol) and Brettphos (13 mg, 0.025mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (60 mg, 0.25 mmol),(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(pyridin-2-yl)methanone(80 mg, 0.25 mmol) in dioxane (5 mL) and Cs₂CO₃ (163 mg, 0.500 mmol)were added, and the resulting mixture was stirred at 100° C. for 6 h. Ablack brown mixture was formed. LCMS (Rt=0.634 min; MS Calc'd: 480.2; MSFound: 481.3 [M+H]⁺). The reaction mixture was filtered. The mixture waspurified by prep-HPLC (normal phase, hexane-IPA (40-100% B)) andlyophilized to giveN,N-dimethyl-4-(6-((1-picolinoyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide(10.3 mg, yield: 9%) as an off-white solid. LCMS (Shimadzu LCMS 2010,mobile phase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5%[water+0.05% NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under thiscondition for 1.1 min, finally changed to 100% [water+0.05% NH₃.H₂O] and0% [MeCN] and under this condition for 0.09 min.) purity is 95.63%,Rt=2.629 min; MS Calc'd.: 480.2, MS Found: 481.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.98 (6H, s), 3.81-3.99 (2H, m), 4.29-4.45 (2H, m),6.69-6.89 (1H, m), 7.47 (2H, d, J=6.8 Hz), 7.48-7.59 (1H, m), 7.70 (2H,d, J=6.8 Hz), 7.79 (1H, d, J=6.8 Hz), 7.90 (1H, d, J=6.8 Hz), 8.02 (1H,t, J=6.4 Hz), 8.26 (1H, br s), 8.42 (1H, s), 8.62 (1H, s), 9.21 (1H, brs). ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 2.92 (3H, s), 2.96 (3H, s),3.79-3.91 (2H, m), 4.29-4.43 (2H, m), 6.66-6.87 (1H, m), 7.44 (2H, d,J=7.6 Hz), 7.47-7.55 (1H, m), 7.65 (2H, d, J=7.6 Hz), 7.74 (1H, d, J=7.2Hz), 7.85 (1H, d, J=8.0 Hz), 7.97 (1H, t, J=6.8 Hz), 8.07 (1H, br s),8.33 (1H, s), 8.54 (1H, s). ¹H NMR (400 MHz, DMSO-d₆+D₂O, t=80° C.) δ2.95 (6H, s), 4.38 (2H, t, J=4.0 Hz), 3.76-3.85 (2H, m, overlapped withH₂O), 6.75 (1H, d, J=8.4 Hz), 7.40-7.49 (3H, m), 7.59-7.64 (2H, m), 7.69(1H, dd, J=8.0, 1.2 Hz), 7.79-7.83 (1H, m), 7.90-7.97 (1H, m), 8.01 (1H,s), 8.24, 8.60 (0.8H+0.2H, s), 8.30 (1H, s), 8.50-8.53 (1H, m).

Example 96:4-(6-((1-(3-hydroxy-2,2-dimethylpropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of 3-acetoxy-2,2-dimethylpropanoic acid

3-Hydroxy-2,2-dimethylpropanoic acid (1.00 g, 8.47 mmol) was slowlyadded acetyl chloride (1.33 g, 16.9 mmol) at 0° C. The reaction mixturewas then warmed to 20° C., stirred at 20° C. for 16 h under N₂atmosphere. The colorless solution was formed gradually. Acetyl chloridewas removed under reduced pressure to afford3-acetoxy-2,2-dimethylpropanoic acid (1.30 g, yield: 96%) as a whitegum. ¹H NMR (400 MHz, CDCl₃) δ 1.26 (6H, s), 2.06 (3H, s), 4.12 (2H, s).

Step 2: Preparation of3-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate

In a separate vial, to a solution of 3-acetoxy-2,2-dimethylpropanoicacid (447 mg, 2.79 mmol), DMF (25 mg, 0.35 mmol) in DCM (6 mL) was addedoxalyl chloride (443 mg, 3.49 mmol). The reaction mixture was stirred at20° C. for 0.5 hour. A light yellow solution was formed. The mixture wasconcentrated to give crude 3-chloro-2,2-dimethyl-3-oxopropyl acetate asa yellow oil. To a solution of7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (150 mg, 0.698 mmol) inDCM (6 mL) was added TEA (353 mg, 3.49 mmol). The reaction mixture wascooled to 0° C. and then added 3-chloro-2,2-dimethyl-3-oxopropyl acetatein DCM (6 mL) dropwise. The reaction mixture was then warmed to 20° C.,stirred at 20° C. for 2 h under N₂ atmosphere. The colorless solutionturned to orange gradually. LCMS (Rt=0.636 min, MS Calc'd.: 356.0; MSFound: 356.8 [M+H]⁺). The reaction mixture was concentrated. The residuewas purified by Combi Flash (80% DCM in pentane (1% TEA as an additive))to afford the product3-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate (330 mg, yield: 74%) as a red gum. ¹H NMR (400 MHz, CDCl₃) δ1.41 (6H, s), 2.09 (3H, s), 3.99 (2H, t, J=4.4 Hz), 4.24 (2H, s), 4.46(2H, t, J=4.4 Hz), 8.04 (1H, d, J=2.0 Hz), 8.28 (1H, d, J=2.0 Hz).

Step 3: Preparation of3-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate

A mixture of Pd₂(dba)₃ (24 mg, 0.026 mmol) and Brettphos (28 mg, 0.052mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-Aminopyridin-3-yl)-N,N-dimethylbenzamide (170 mg, 0.704 mmol),3-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate (330 mg, 0.517 mmol) in dioxane (8 mL) and Cs₂CO₃ (337 mg, 1.03mmol) were added and the resulting mixture was stirred at 100° C. for 10h. A black brown mixture was formed. LCMS showed the purity of thedesired product (Rt=0.557 min; MS Calc'd: 517.2; MS Found: 518.2[M+H]⁺). The reaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by Combi Flash (1% TEA in EtOAc)to give3-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate (100 mg, yield: 37%) as a red gum. ¹H NMR (400 MHz, CDCl₃) δ1.43 (6H, s), 2.06 (3H, s), 3.04 (3H, s), 3.13 (3H, s), 4.02 (2H, t,J=4.0 Hz), 4.24 (2H, s), 4.47 (2H, t, J=4.4 Hz), 6.58 (1H, br s), 6.79(1H, d, J=8.8 Hz), 7.47-7.54 (4H, m), 7.74 (1H, dd, J=8.8, 2.0 Hz), 8.07(1H, d, J=2.8 Hz), 8.28 (1H, d, J=2.8 Hz), 8.41 (1H, d, J=2.0 Hz).

Step 4: Preparation of4-(6-((1-(3-hydroxy-2,2-dimethylpropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a solution of3-(7-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethyl-3-oxopropylacetate (70 mg, 0.14 mmol) in dioxane (4 mL) was added MeOH (635 mg,19.8 mmol). Then the yellow solution was added K₂CO₃ (56 mg, 0.41 mmol),stirred at 20° C. for 4 h. LCMS (Rt=0.505 min; MS Calc'd: 475.2; MSFound: 476.2 [M+H]⁺). The reaction mixture was concentrated. The residuewas purified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilizedto afford4-(6-((1-(3-hydroxy-2,2-dimethylpropanoyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(22.7 mg, yield: 35%) as a white solid.

LCMS (Shimadzu LCMS 2010, Mobile phase: from 100% [water+0.04% TFA] to40% [water+0.04% TFA] and 60% [MeCN+0.02% TFA] in 1.35 min, then underthis condition for 0.9 min, finally changed to 100% [water+0.04% TFA]and under this condition for 0.75 min.) purity is 98.68%, Rt=1.403 min;MS Calc'd.: 475.2; MS Found: 476.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.28 (6H, s), 2.98 (6H, s), 3.54 (2H, d, J=5.6 Hz), 4.04 (2H, t, J=4.0Hz), 4.35 (2H, t, J=3.6 Hz), 4.97 (1H, t, J=5.6 Hz), 6.86 (1H, d, J=8.4Hz), 7.47 (2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.4 Hz), 7.93 (1H, dd,J=8.8, 2.4 Hz), 8.24 (1H, d, J=2.4 Hz), 8.43 (1H, d, J=2.8 Hz), 8.49(1H, d, J=2.0 Hz), 9.16 (1H, br s).

Example 97:N,N-dimethyl-4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

Step 1: Preparation of1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethylpropan-1-one

To a solution of 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (100mg, 0.465 mmol) in DCM (5 mL) was added TEA (235 mg, 2.33 mmol). Thereaction mixture was cooled to 0° C. and then added pivaloyl chloride(2.3 mL, 18 mmol) dropwise. The reaction mixture was then warmed to 20°C., stirred at 20° C. for 18 h under N₂ atmosphere. The colorlesssolution turned to suspension. LCMS showed the purity of the desiredproduct (Rt=0.656 min; MS Calc'd: 298.0; MS Found: 299.6 [M+H]⁺). Thereaction mixture was concentrated. The residue was purified by CombiFlash (40% DCM in pentane (1% TEA as an additive)), then the impureproduct was purified by prep-TLC (1% TEA in DCM) to afford1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethylpropan-1-one(30 mg, yield: 22%) as a yellow gum. ¹H NMR (400 MHz, CDCl₃) δ 1.39 (9H,s), 4.02 (2H, t, J=4.8 Hz), 4.45 (2H, t, J=4.8 Hz), 8.02 (1H, d, J=2.4Hz), 8.37 (1H, d, J=2.0 Hz).

Step 2: Preparation ofN,N-dimethyl-4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide

A mixture of Pd₂(dba)₃ (5 mg, 0.005 mmol) and Brettphos (5 mg, 0.01mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-Aminopyridin-3-yl)-N,N-dimethylbenzamide (24 mg, 0.10 mmol),1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethylpropan-1-one(30 mg, 0.10 mmol) in dioxane (2 mL) and Cs₂CO₃ (65 mg, 0.20 mmol) wereadded and the resulting mixture was stirred at 100° C. for 6 h. A blackbrown mixture was formed. LCMS (Rt=0.677 min; MS Calc'd: 459.2; MSFound: 460.3 [M+H]⁺). The reaction mixture was filtered. The mixture waspurified by prep-HPLC (normal phase, hexane-IPA (10-100% B)) andlyophilized to give impure product (25 mg), then purified by prep-HPLC(0.05% NH₃.H₂O as an additive) and lyophilized to giveN,N-dimethyl-4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)benzamide(11.2 mg, yield: 24%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 97.48%, Rt=2.902 min; MSCalc'd.: 459.2, MS Found: 460.2 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ 1.39(9H, s), 3.04 (3H, s), 3.13 (3H, s), 4.05 (2H, t, J=4.0 Hz), 4.47 (2H,t, J=4.4 Hz), 6.41 (1H, br s), 6.80 (1H, d, J=8.8 Hz), 7.49 (2H, d,J=8.4 Hz), 7.55 (2H, d, J=8.4 Hz), 7.75 (1H, dd, J=8.4, 2.4 Hz), 8.07(1H, d, J=2.4 Hz), 8.30 (1H, d, J=2.8 Hz), 8.42 (1H, d, J=1.6 Hz).

Example 98: tert-butyl(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate

Step 1: Preparation of 3-((tert-butoxycarbonyl)amino)benzoic acid

To a solution of 3-aminobenzoic acid (5.00 g, 36.5 mmol), TEA (10 mL,72.9 mmol), H₂O (42 mL) in dioxane (84 mL) was added Boc₂O (12.6 mL,54.7 mmol) at 20° C. Reaction mixture was allowed to stir at 20° C. for18 h. The solution became colorless to light yellow. TLC showed absenceof starting material. 1,4-Dioxane was removed under reduced pressure andHCl (60 mL, 3M) was added drop-wise. The white precipitate was filteredout, washed with hexane (50 mL×3) and dried to afford3-((tert-butoxycarbonyl)amino)benzoic acid (8.64 g, yield: 100%) as awhite solid. ¹H NMR (400 MHz, CDCl₃) δ 1.53 (9H, s), 6.64 (1H, br s),7.40 (1H, t, J=8.0 Hz), 7.66-7.81 (2H, m), 7.97-8.02 (1H, s), 11.99 (1H,br s).

Step 2: Preparation of tert-butyl(3-((5-bromopyridin-3-yl)carbamoyl)phenyl)carbamate

3-((Tert-butoxycarbonyl)amino)benzoic acid (500 mg, 2.11 mmol) and5-bromopyridin-3-amine (365 mg, 2.11 mmol) in pyridine (8 mL) was addedEDCI (607 mg, 3.17 mmol). The mixture was stirred at 20° C. for 18 h.The color of solution became tangerine gradually. Crude LCMS showed thepurity of desired product (Rt=0.813 min; MS Calc'd: 391.0; MS Found:394.1 [M+H]⁺). Pyridine was removed under reduced pressure. Afteraddition of sat.NaHCO₃ (30 mL) to the residue, the mixture was extractedwith DCM (20 mL×3). The organic layer was dried over anhydrous Na₂SO₄,and concentrated in vacuum. The residue was purified by Combi Flash (1%TEA in DCM) to give tert-butyl(3-((5-bromopyridin-3-yl)carbamoyl)phenyl)carbamate (750 mg, yield: 91%)as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.54 (9H, s), 6.67 (1H,br s), 7.38-7.51 (2H, m), 7.57 (1H, d, J=7.8 Hz), 8.02 (1H, s), 8.14(1H, br s), 8.45 (1H, d, J=2.0 Hz), 8.57 (1H, t, J=2.0 Hz), 8.62 (1H, d,J=2.0 Hz).

Step 3: Preparation of tert-butyl(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate

A mixture of Pd₂(dba)₃ (13 mg, 0.015 mmol, 3 mol %) and Brettphos (16mg, 0.029 mmol, 6 mol %) in 1,4-dioxane (1 mL) was stirred at 50° C. for10 min. Tert-butyl (3-((5-bromopyridin-3-yl)carbamoyl)phenyl)carbamate(190 mg, 0.484 mmol), 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (117mg, 0.484 mmol) in dioxane (3 mL) and Cs₂CO₃ (316 mg, 0.969 mmol) wereadded and the resulting mixture was stirred at 100° C. for 16 h. Thecolor of mixture was black brown. LCMS is 66% (Rt=0.670 min; MS Calc'd:552.2; MS Found: 553.0 [M+H]⁺). The reaction mixture was diluted withEtOAc (20 mL), filtered and concentrated to give crude producttert-butyl(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamateas an orange gum and directly used to next step. Crude product (50 mg)was purified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilizedto afford tert-butyl(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate(2.40 mg) as a white solid. LCMS (Shimadzu LCMS 2010, mobile phase: from100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05% NH₃.H₂O] and95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finallychanged to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] and under thiscondition for 0.09 min.) purity is 98.48%, Rt=3.319 min; MS Calc'd.:552.2, MS Found: 553.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.50 (9H, s),7.01 (1H, d, J=8.8 Hz), 7.43 (1H, t, J=8.0 Hz), 7.48 (2H, d, J=8.0 Hz),7.57 (1H, d, J=7.8 Hz), 7.62 (1H, d, J=8.8 Hz), 7.73 (2H, d, J=8.0 Hz),8.01 (1H, dd, J=8.8, 3.2 Hz), 8.04-8.07 (1H, m), 8.47 (1H, d, J=2.0 Hz),8.59 (1H, d, J=2.4 Hz), 8.67 (1H, t, J=2.0 Hz), 8.70 (1H, d, J=2.0 Hz),9.50 (1H, br s), 9.58 (1H, br s), 10.41 (1H, br s). ¹H NMR (400 MHz,DMSO-d₆+D₂O) δ 1.43 (9H, s), 2.92 (3H, s), 2.95 (3H, s), 6.96 (1H, d,J=9.2 Hz), 7.39 (1H, t, J=7.6 Hz), 7.44 (2H, d, J=8.0 Hz), 7.49-7.58(2H, m), 7.69 (2H, d, J=8.4 Hz), 7.93-7.99 (2H, m), 8.39 (1H, d, J=2.4Hz), 8.52 (1H, d, J=2.4 Hz), 8.58 (1H, d, J=2.4 Hz), 8.67 (1H, t, J=2.0Hz).

Example 99:4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a stirred solution of tert-butyl(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate(267 mg, 0.483 mmol) in DCM (6 mL) was added TFA (4 M, 10 mL) at 20° C.The red solution precipitated. Then reaction mixture was stirred for 2h. LCMS (Rt=0.563 min; MS Calc'd: 452.2; MS Found: 452.9 [M+H]⁺). Themixture was concentrated. The residue was purified by Combi Flash (8%MeOH in DCM (1% TEA as an additive)) to afford4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(210 mg, yield: 96%) as an off-white solid. Crude product (50 mg) waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized toafford4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.88 mg) as a white solid. LCMS (Shimadzu LCMS 2010, mobile phase: from100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05% NH₃.H₂O] and95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finallychanged to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] and under thiscondition for 0.09 min.) purity is 99.55%, Rt=2.547 min; MS Calc'd.:452.2, MS Found: 453.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.96 (3H, s),2.99 (3H, s), 5.35 (2H, br s), 6.77 (1H, d, J=8.8 Hz), 6.99 (1H, d,J=8.8 Hz), 7.07-7.13 (2H, m), 7.14 (1H, t, J=8.4 Hz), 7.48 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0 Hz), 8.00 (1H, dd, J=8.4, 1.6 Hz), 8.44-8.47(1H, m), 8.57-8.60 (1H, m), 9.62-8.67 (1H, m), 8.71-8.73 (1H, m), 9.48(1H, br s), 10.26 (1H, br s).

Example 100:(E)-4-(6-((5-(3-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(80 mg, 0.177 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (25 mg,0.194 mmol) in pyridine (2 mL) was added EDCI (51 mg, 0.265 mmol). Themixture was stirred at 25° C. for 16 h. A dark red solution was formedgradually. LCMS showed the purity of desired product (Rt=0.568 min; MSCalc'd: 563.3; MS Found: 564.0 [M+H]⁺). Pyridine was removed underreduced pressure. The crude product was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) and lyophilized to give impure product (15 mg),then purified by prep-HPLC (0.225% FA as an additive) again andlyophilized to give(E)-4-(6-((5-(3-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(12.4 mg, yield: 12%) as alight yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is97.29%, Rt=1.303 min; MS Calc'd.: 563.3; MS Found: 564.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.19 (6H, s), 2.97 (6H, s), 3.07 (2H, dd, J=8.4,1.6 Hz), 6.25-6.33 (1H, m), 6.73-6.82 (1H, m), 7.00 (1H, d, J=8.0 Hz),7.45-7.52 (3H, m), 7.67 (1H, d, J=7.6 Hz), 7.73 (2H, d, J=8.8 Hz),7.87-7.93 (1H, m), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.16 (1H, s), 8.20 (1H,t, J=2.0 Hz), 8.48 (1H, d, J=2.4 Hz), 8.58 (1H, d, J=2.8 Hz), 8.67 (1H,t, J=2.0 Hz), 8.72 (1H, d, J=2.0 Hz), 9.50 (1H, br s), 10.28 (1H, br s),10.45 (1H, br s). ¹H NMR (400 MHz, DMSO-d₆+D₂O) δ 2.36 (6H, s), 2.94(3H, s), 2.97 (3H, s), 3.34 (2H, dd, J=6.0), 6.33 (1H, d, J=15.6 Hz),6.70-6.81 (1H, m), 6.98 (1H, d, J=9.2 Hz), 7.43-7.54 (3H, m), 7.66 (1H,d, J=8.0 Hz), 7.71 (2H, d, J=8.4 Hz), 7.82 (1H, dd, J=7.8, 1.6 Hz), 7.98(1H, dd, J=8.8, 2.4 Hz), 8.15-8.23 (2H, m), 8.43 (1H, d, J=2.0 Hz), 8.55(1H, d, J=2.4 Hz), 8.62 (1H, d, J=2.4 Hz), 8.70 (1H, t, J=2.4 Hz).

Example 101: tert-butyl(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate

Step 1: Preparation of 3-(3-((tert-butoxycarbonyl)amino)phenyl)propanoicacid

To a solution of 3-(3-aminophenyl)propanoic acid (850 mg, 5.15 mmol),TEA (1.4 mL, 10.3 mmol), H₂O (7 mL) in dioxane (14 mL) was added Boc₂O(1.8 mL, 7.72 mmol) at 20° C. Reaction mixture was allowed to stir for18 h. The colorless solution became yellow gradually. LCMS is 95%(RT=0.759 min; MS Calc'd: 265.1; MS Found: 288.1 [M+Na]+). 1,4-dioxanewas removed under reduced pressure and HCl solution (5 mL, 2 M) wasadded drop-wise. After addition of H₂O (40 mL), the mixture wasextracted with DCM (20 mL×3). The organic layer was dried over anhydrousNa₂SO₄, and concentrated to afford3-(3-((tert-butoxycarbonyl)amino)phenyl)propanoic acid (1.36 g, yield:99%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.52 (9H, s), 2.68(2H, t, J=8.0 Hz), 2.93 (2H, t, J=8.0 Hz), 6.57 (1H, s), 6.89 (1H, d,J=7.6 Hz), 7.12-7.24 (2H, m), 7.28 (1H, br s).

Step 2: Preparation of tert-butyl(3-(3-((5-bromopyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate

3-(3-((Tert-butoxycarbonyl)amino)phenyl)propanoic acid (182 mg, 0.688mmol) and 5-bromopyridin-3-amine (100 mg, 0.578 mmol) in pyridine (4 mL)was added EDCI (166 mg, 0.867 mmol). The mixture was stirred at 20° C.for 20 h. The color of solution became dark red gradually. Crude LCMSshowed the purity of desired product (Rt=0.825 min; MS Calc'd: 419.1; MSFound: 442.2 [M+Na]⁺). Pyridine was removed under reduced pressure. Theresidue was purified by Combi Flash (1% TEA in DCM) to give tert-butyl(3-(3-((5-bromopyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate (175 mg,yield: 72%) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.51 (9H,s), 2.66 (2H, t, J=7.6 Hz), 2.98 (2H, t, J=8.0 Hz), 6.67 (1H, s), 6.87(1H, d, J=7.6 Hz), 7.03 (1H, d, J=8.4 Hz), 7.17 (1H, t, J=7.6 Hz), 7.42(1H, br s), 7.87 (1H, br s), 8.35 (2H, t, J=2.4 Hz), 8.39 (1H, t, J=2.0Hz).

Step 3: Preparation of tert-butyl(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate

A mixture of Pd₂(dba)₃ (15 mg, 0.017 mmol, 4 mol %) and Brettphos (18mg, 0.033 mmol, 8 mol %) in 1,4-dioxane (1 mL) was stirred at 50° C. for10 min. Tert-butyl(3-(3-((5-bromopyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate (175 mg,0.416 mmol), 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (100 mg,0.416 mmol) in dioxane (6 mL) and Cs₂CO₃ (271 mg, 0.833 mmol) were addedand the resulting mixture was stirred at 100° C. for 18 h. A black brownmixture was formed. LCMS (Rt=0.661 min; MS Calc'd: 580.3; MS Found:581.0 [M+H]⁺). The reaction mixture was diluted with ethyl acetate (20mL), filtered and concentrated to give an orange gum. Crude product (50mg) was purified by prep-HPLC (0.05% NH₃.H₂O as an additive) andlyophilized to afford tert-butyl(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate(2.40 mg) as a white solid. Another crude product did not purify, anddirectly used to next step. LCMS (Shimadzu LCMS 2010, mobile phase: from100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05% NH₃.H₂O] and95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finallychanged to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] and under thiscondition for 0.09 min.) purity is 97.29%, Rt=3.363 min; MS Calc'd.:580.3, MS Found: 581.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.44 (9H, s),2.60-2.65 (2H, m, overlapped with DMSO-d₆), 2.84 (2H, t, J=8.0 Hz), 2.95(6H, s), 6.83 (1H, d, J=7.2 Hz), 6.95 (1H, d, J=8.4 Hz), 7.13 (1H, t,J=7.6 Hz), 7.20 (1H, d, J=8.8 Hz), 7.41 (1H, s), 7.46 (2H, d, J=8.0 Hz),7.70 (2H, d, J=8.4 Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.30 (1H, d, J=2.4Hz), 8.48 (1H, t, J=2.0 Hz), 8.54 (1H, d, J=2.8 Hz), 8.62 (1H, d, J=2.4Hz), 9.26 (1H, br s), 9.43 (1H, br s), 10.09 (1H, br s).

Example 102:4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a stirred solution of tert-butyl(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate(248 mg, 0.427 mmol) in DCM (4 mL) was added HCl/EtOAc (4 M, 8.5 mL) at20° C. The red solution precipitated. Then the reaction mixture wasstirred for 16 h. LCMS the purity of the desired product (Rt=0.627 min;MS Calc'd: 480.2; MS Found: 481.1 [M+H]⁺). The mixture was concentrated.The residue (100 mg) was purified by prep-TLC (MeOH:DCM (1% TEtOAc as anadditive)=1:9) to give impure product (60 mg) as an off-white solid,then purified by prep-HPLC (0.05% NH₃.H₂O as an additive) again andlyophilized to afford4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.23 mg) as a white solid. LCMS (Shimadzu LCMS 2010, Mobile phase: from90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04% TFA]and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA]and under this condition for 0.75 min.) purity is 96.20%, Rt=1.343 min;MS Calc'd.: 480.3; MS Found: 481.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ2.58 (2H, t, J=8.8 Hz, overlapped with DMSO-d₆), 2.74 (2H, t, J=8.0 Hz),2.96 (6H, s), 4.93 (2H, br s), 6.33-6.44 (3H, m), 6.89 (1H, t, J=7.6Hz), 6.96 (1H, d, J=8.8 Hz), 7.46 (2H, d, J=8.4 Hz), 7.70 (2H, d, J=8.4Hz), 7.96 (1H, dd, J=8.8, 2.4 Hz), 8.31 (1H, d, J=2.0 Hz), 8.48 (1H, t,J=2.0 Hz), 8.54 (1H, d, J=2.8 Hz), 8.62 (1H, d, J=2.4 Hz), 9.41 (1H, brs), 10.05 (1H, br s).

Example 103:(E)-4-(6-((5-(3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(50 mg, 0.104 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (16 mg,0.12 mmol) in pyridine (2 mL) was added EDCI (30 mg, 0.156 mmol). Themixture was stirred at 20° C. for 16 h. A dark red solution was formedgradually. LCMS showed the purity of desired product (Rt=0.666 min; MSCalc'd: 591.3; MS Found: 614.4 [M+Na]⁺). Pyridine was removed underreduced pressure. The crude product was purified by prep-TLC (MeOH:DCM(1% TEA as an additive)=1:10) to give impure product (50 mg), thenpurified by prep-HPLC (0.225% formic acid as an additive) again andlyophilized to give(E)-4-(6-((5-(3-(3-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(5.0 mg, yield: 8%) as an off-white solid. LCMS (Shimadzu LCMS 2010,mobile phase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5%[water+0.05% NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under thiscondition for 1.1 min, finally changed to 100% [water+0.05% NH₃.H₂O] and0% [MeCN] and under this condition for 0.09 min.) purity is 100%,Rt=2.838 min; MS Calc'd.: 591.3, MS Found: 592.3 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.19 (6H, s), 2.66 (2H, t, J=8.0 Hz), 2.90 (2H, t, J=7.2Hz), 2.97 (6H, s), 3.08 (2H, d, J=5.6 Hz), 6.27 (1H, d, J=15.2 Hz),6.63-6.78 (1H, m), 6.97 (1H, t, J=8.4 Hz), 7.23 (1H, t, J=8.0 Hz),7.41-7.52 (3H, m), 7.59 (1H, s), 7.72 (2H, d, J=8.0 Hz), 7.99 (1H, dd,J=8.4, 2.4 Hz), 8.16 (1H, s), 8.25-8.38 (1H, m), 8.43-8.69 (3H, m), 9.45(1H, br s), 10.02 (1H, br s), 10.11 (1H, br s).

Example 104: tert-butyl(3-(((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamate

Step 1: Preparation of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate

To a solution of 5-bromopicolinonitrile (5.00 g, 27.3 mmol), CoCl₂.6H₂O(9.75 g, 40.9 mmol) in MeOH (65 mL) was added NaBH₄ (3.10 g, 81.9 mmol)at 0° C., and the mixture was stirred at 0° C. for 1 h under N₂atmosphere. TLC showed the reaction was completed. To the mixture wasadded H₂O (8 mL) and Boc₂O (11.9 g, 54.6 mmol). The mixture was stirredat 70° C. for 15 h. The dark red mixture turned to black, and produced apurple solid. TLC indicated the reaction was completed. The resultingmixture was concentrated. The residue was diluted with H₂O (130 mL) andDCM (130 mL) then filtered. The aqueous layer was extracted with DCM(120 mL×2). The combined organic layer was dried over anhydrous Na₂SO₄and concentrated under reduced pressure. The residue was purified byCombi Flash (25% EtOAc in pentane) to give tert-butyl((5-bromopyridin-2-yl)methyl)carbamate (4.11 g, yield: 52%) as a yellowsolid. ¹H NMR (400 MHz, CDCl₃) δ 1.45 (9H, s), 4.39 (2H, d, J=5.6 Hz),5.47 (1H, br s), 7.19 (1H, d, J=8.0 Hz), 7.77 (1H, dd, J=8.4, 2.4 Hz),8.59 (1H, d, J=2.0 Hz).

Step 2: Preparation of (5-bromopyridin-2-yl)methanamine

A mixture of tert-butyl ((5-bromopyridin-2-yl)methyl)carbamate (4.10 g,14.3 mmol) in EtOAc (10 mL) was added HCl/EtOAc (1 M in EtOAc, 70 mL)and the reaction was stirred at 25° C. for 15 h. The yellow solutionproduced a light yellow suspension. TLC showed the reaction wascompleted. Concentrated in vacuum to give(5-bromopyridin-2-yl)methanamine (3.63 g, crude) as a light yellowsolid. ¹H NMR (400 MHz, d₆-DMSO) δ 4.67 (2H, q, J=5.6 Hz), 8.04 (1H, d,J=8.8 Hz), 8.66 (1H, dd, J=8.4, 2.4 Hz), 9.06 (2H, br s), 9.27 (1H, d,J=2.0 Hz).

Step 3: Preparation of tert-butyl(3-(((5-bromopyridin-2-yl)methyl)carbamoyl)phenyl)carbamate

A solution of 3-((tert-butoxycarbonyl)amino)benzoic acid (696 mg, 2.94mmol) in pyridine (8 mL) was added (5-bromopyridin-2-yl)methanamine (500mg, 2.67 mmol) and EDCI (1.02 g, 5.34 mmol) and the reaction was stirredat 50° C. for 15 h. The yellow solution turned to black. Crude LCMS(Rt=0.696 min; MS Calc'd: 405.1; MS Found: 405.7 [M+H]⁺). The mixturewas concentrated in vacuum. The residue was purified by Combi Flash (86%DCM in pentane) to give tert-butyl(3-(((5-bromopyridin-2-yl)methyl)carbamoyl)phenyl)carbamate (218 mg,yield: 20%) as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 1.56 (9H, s),4.71 (2H, d, J=5.2 Hz), 6.57 (1H, s), 7.30 (1H, s), 7.38 (1H, t, J=8.0Hz), 7.51 (1H, d, J=8.0 Hz), 7.59 (1H, d, J=7.6 Hz), 7.79-7.82 (2H, m),8.63 (1H, d, J=2.4 Hz).

Step 4: Preparation of tert-butyl(3-(((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamate

A mixture of Pd₂(dba)₃ (15 mg, 0.016 mmol, 3 mol %) and Brettphos (17mg, 0.032 mmol, 6 mol %) in dioxane (8 mL) was stirred at 50° C. for 10min. Tert-butyl(3-(((5-bromopyridin-2-yl)methyl)carbamoyl)phenyl)carbamate (218 mg,0.536 mmol), 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (129 mg,0.537 mmol) in dioxane (8 mL) and Cs₂CO₃ (350 mg, 1.07 mmol) were addedand the resulting mixture was stirred at 100° C. for 15 h. The dark redsolution turned to brown mixture. Crude LCMS (Rt=0.736 min; MS Calc'd:566.3; MS Found: 567.3 [M+H]⁺). The reaction mixture was diluted withEtOAc (30 mL), dried over Na₂SO₄, filtered and concentrated. The residuewas purified by Combi Flash (5% MeOH in DCM) and lyophilized to givetert-butyl(3-(((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamate(145 mg, yield: 48%) as a light yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is98.09%, Rt=1.845 min; MS Calc'd.: 566.3; MS Found: 567.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.48 (9H, s), 2.97 (6H, s), 4.50 (2H, d, J=5.2 Hz),6.95 (1H, d, J=8.4 Hz), 7.26 (1H, d, J=8.8 Hz), 7.34 (1H, t, J=8.0 Hz),7.46-7.57 (4H, m), 7.71 (2H, d, J=8.0 Hz), 7.97 (1H, dd, J=9.2, 2.8 Hz),8.02 (1H, s), 8.18 (1H, dd, J=8.8, 2.8 Hz), 8.55 (1H, s), 8.81 (1H, s),8.95-8.98 (1H, m), 9.44 (1H, s), 9.50 (1H, s).

Example 105:4-(6-((6-((3-aminobenzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of tert-butyl(3-(((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-2-yl)methyl)carbamoyl)phenyl)carbamate(140 mg, 0.247 mmol) in EtOAc (3 mL) was added HCl/EtOAc (1 M in EtOAc,5 mL) and the reaction was stirred at 25° C. for 2 h. The yellowsolution produced a light yellow solid. TLC showed the reaction wascompleted. The mixture was concentrated in vacuum. The residue waslyophilized to give4-(6-((6-((3-aminobenzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(151 mg, yield: 99%) as a yellow solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is97.02%, Rt=1.592 min; MS Calc'd.: 466.2; MS Found: 467.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.95 (3H, s), 2.98 (3H, s), 4.78 (2H, d, J=6.0 Hz),7.16 (1H, d, J=8.8 Hz), 7.48-7.51 (3H, m), 7.59 (1H, t, J=8.0 Hz), 7.76(2H, d, J=8.4 Hz), 7.81 (1H, s), 7.88 (1H, d, J=9.2 Hz), 7.94 (1H, d,J=8.0 Hz), 8.11 (1H, dd, J=8.8, 2.8 Hz), 8.54 (1H, dd, J=9.2, 2.8 Hz),8.67 (1H, d, J=2.4 Hz), 9.48 (1H, d, J=3.2 Hz), 9.58 (1H, t, J=4.8 Hz).

Example 106:(E)-4-(6-((6-((3-(4-(dimethylamino)but-2-enamido)benzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A solution of4-(6-((6-((3-aminobenzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(151 mg, 0.246 mmol) in pyridine (4 mL), was added(E)-4-(dimethylamino)but-2-enoic acid (49 mg, 0.30 mmol) and EDCI (95mg, 0.49 mmol). And the reaction was stirred at 20° C. for 16 h. Thelight yellow solution turned to dark red. Crude LCMS (Rt=0.626 min; MSCalc'd: 577.3; MS Found: 578.3 [M+H]⁺). Filtered and concentrated invacuum. The residue was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give(E)-4-(6-((6-((3-(4-(dimethylamino)but-2-enamido)benzamido)methyl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(53.1 mg, yield: 37%) as a light yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is97.02%, Rt=1.418 min; MS Calc'd.: 577.3; MS Found: 578.4 [M+H]⁺. ¹H NMR(400 MHz, d₆-DMSO) δ 2.18 (6H, s), 2.98 (6H, s), 3.06 (2H, d, J=6.4 Hz),4.52 (2H, d, J=5.2 Hz), 6.28 (1H, d, J=15.6 Hz), 6.76 (1H, d, J=15.2Hz), 6.96 (1H, d, J=8.4 Hz), 7.27 (1H, d, J=8.8 Hz), 7.42 (1H, t, J=8.0Hz), 7.47 (1H, s), 7.49 (1H, s), 7.60 (1H, d, J=8.0 Hz), 7.70 (1H, s),7.73 (1H, s), 7.86 (1H, d, J=9.2 Hz), 7.97 (1H, dd, J=8.8, 2.8 Hz), 8.14(1H, s), 8.18 (1H, dd, J=8.4, 2.4 Hz), 8.55 (1H, d, J=2.8 Hz), 8.80 (1H,d, J=3.2 Hz), 9.01 (1H, s), 9.40 (1H, s).

Example 107:4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of tert-butyl(2-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-2-oxoethyl)carbamate

To a suspension of4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(328 mg, 0.523 mmol) in pyridine (5 mL) was added EDCI (100 mg, 0.523mmol). And the resulting mixture was stirred at 20° C. for 18 h. A redsolution was formed. LCMS (Rt=0.611 min; MS Calc'd: 637.6; MS Found:638.2 [M+H]⁺). The reaction solution was concentrated to afford a redsolid. DCM (30 mL) and water (10 mL) was added to the solid. The waterlayer was washed by DCM (30 mL×2). The organic layer was collected andconcentrated to give tert-butyl(2-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-2-oxoethyl)carbamate(260 mg, yield: 69%) as a red solid. Used in the next step withoutpurification.

Step 2: Preparation of4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of tert-butyl(2-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-2-oxoethyl)carbamate(260 mg, 0.483 mmol) and aq. HCl (4 M, 20 mL) was stirred at 10° C. for4 h. A red solution was formed. LCMS is 90% (Rt=0.533 min; MS Calc'd:537.6; MS Found: 538.1 [M+H]⁺). The reaction solution was concentratedto afford4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(201 mg, yield: 51%) as a red solid. Used in the next step withoutpurification. Crude product (105 mg) was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) and lyophilized to afford4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(3.21 mg) as a white solid. LCMS (Shimadzu LCMS 2010, mobile phase: from100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05% NH₃.H₂O] and95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finallychanged to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] and under thiscondition for 0.09 min.) purity is 100%, Rt=2.717 min; MS Calc'd.:537.2, MS Found: 538.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.43-2.45(2H, overlap with DMSO), 2.66-2.68 (2H, m), 2.87 (2H, t, J=7.6 Hz), 2.97(3H, s), 2.98 (3H, s), 6.91 (1H, d, J=8.0 Hz), 6.95 (1H, d, J=7.6 Hz),7.22 (1H, t, J=8.8 Hz), 7.46-7.48 (4H, m), 7.71 (2H, d, J=8.4 Hz), 7.96(1H, dd, J=8.8, 2.4 Hz), 8.03 (1H, d, J=8.4 Hz), 8.09 (1H, dd, J=9.2,2.8 Hz), 8.25 (1H, br s), 8.54 (1H, d, J=2.8 Hz), 8.65 (1H, dd, J=9.2,2.8 Hz), 9.32 (1H, br s), 10.35 (1H, br s).

Example 108:(E)-4-(6-((5-(3-(3-(2-(4-(dimethylamino)but-2-enamido)acetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of4-(6-((5-(3-(3-(2-aminoacetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(80 mg, 0.12 mmol), (E)-4-(dimethylamino)but-2-enoic acid (23 mg, 0.17mmol) and EDCI (45 mg, 0.23 mmol) was added pyridine (5 mL). And theresulting mixture was stirred at 20° C. for 20 h. A red solution wasformed. LCMS is 8% (Rt=2.971 min; MS Calc'd: 648.7; MS Found: 649.3[M+H]⁺). Solvent was removed under reduced pressure to afford a redsolid. Crude product was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give impure product as a brown solid. Thenthe solid was purified by prep-HPLC (0.05% HCl as an additive) andlyophilized to give(E)-4-(6-((5-(3-(3-(2-(4-(dimethylamino)but-2-enamido)acetamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(5.53 mg, yield: 7%) as a yellow solid. LCMS (Shimadzu LCMS 2010, mobilephase: C) 10 mM NH₄HCO₃ in Water; D) MeCN. Gradient: 1% D increase to 5%D within 0.6 min; 5% D increase to 100% D within 3.4 min; then back to1% D within 0.3 min. Flow rate 0.8 mL/min) purity is 100%, Rt=2.439 min;MS Calc'd.: 648.3, MS Found: 649.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ2.73 (3H, s), 2.74 (3H, s), 2.89 (2H, t, J=7.6 Hz), 2.75-2.79 (2H, m),2.95 (3H, s), 2.98 (3H, s), 3.96 (2H, d, J=6.0 Hz), 4.30 (2H, t, J=5.8Hz), 6.19-6.25 (1H, m), 6.30 (1H, d, J=11.6 Hz), 6.96 (1H, d, J=7.6 Hz),7.08 (1H, d, J=9.6 Hz), 7.22 (1H, t, J=7.6 Hz), 7.43 (1H, d, J=8.0 Hz),7.48-7.50 (3H, m), 7.73 (2H, d, J=8.0 Hz), 7.92 (1H, d, J=8.8 Hz), 8.10(1H, dd, J=8.8, 2.0 Hz), 8.23 (1H, d, J=8.4 Hz), 8.51 (1H, d, J=1.6 Hz),8.75 (1H, t, J=4.8 Hz), 8.86 (1H, br s), 10.13 (2H, br s), 10.50 (1H, brs), 11.28 (1H, br s).

Example 109:N-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide

Step 1: Preparation of tert-butyl4-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamoyl)piperidine-1-carboxylate

To a mixture of4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(209 mg, 0.333 mmol) 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid(76 mg, 0.33 mmol) and EDCI (96 mg, 0.50 mmol) was added pyridine (10mL), and then stirred 20° C. for 20 h. A red mixture was formed. LCMS(Rt=0.657 min; MS Calc'd: 691.3; MS Found: 692.5 [M+H]⁺). Solvent wasremoved under reduced pressure to give a red solid. DCM (15 mL) andwater (15 mL) was added to the solid. The water layer was washed by DCM(30 mL×4). The organic layer was collected and concentrated to givetert-butyl4-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamoyl)piperidine-1-carboxylate(235 g, yield: 73%) as a red solid.

Step 2: Preparation ofN-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide

A mixture of tert-butyl4-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamoyl)piperidine-1-carboxylate(235 mg, 0.339 mmol) and aq. HCl (4 M, 20 mL) was stirred at 20° C. for2 h. A red solution was formed. LCMS (Rt=0.540 min; MS Calc'd: 591.3; MSFound: 592.2 [M+H]⁺). The reaction solution was concentrated to giveN-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide(250 mg, yield: 99%) as a red solid. Used in the next step withoutpurification. Crude product (50 mg) was purified by prep-HPLC (0.05% HClas an additive) and lyophilized to affordN-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide(2.15 mg) as a yellow solid. LCMS (Shimadzu LCMS 2010, mobile phase: C)10 mM NH₄HCO₃ in Water; D) MeCN. Gradient: 1% D increase to 5% D within0.6 min; 5% DB increase to 100% D within 3.4 min; then back to 1% Dwithin 0.3 min. Flow rate 0.8 mL/min) purity is 96.71%, Rt=2.324 min; MSCalc'd.: 591.3, MS Found: 592.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ1.75-1.85 (2H, m), 1.90-1.95 (2H, m), 2.61-2.66 (1H, m), 2.73 (2H, t,J=7.2 Hz), 2.88 (4H t, J=7.2 Hz), 2.95 (3H, s), 2.99 (3H, s), 3.28-3.33(2H, m), 6.95 (1H, d, J=8.0 Hz), 7.05 (1H, d, J=8.8 Hz), 7.20 (1H, t,J=8.0 Hz), 7.40 (1H, d, J=7.6 Hz), 7.49 (2H, d, J=8.8 Hz), 7.55 (1H, s),7.73 (2H, d, J=8.0 Hz), 7.93 (1H, d, J=8.4 Hz), 8.07 (1H, dd, J=9.2, 2.0Hz), 8.20 (1H, dd, J=8.8, 1.6 Hz), 8.51 (1H, d, J=1.6 Hz), 8.61 (1H, brs), 8.83 (1H, s), 8.91 (1H, br s), 9.97 (1H, br s), 10.08 (1H, br s),11.08 (1H, br s).

Example 110:(E)-1-(4-(dimethylamino)but-2-enoyl)-N-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide

To a mixture ofN-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide(200 mg, 0.271 mmol), (E)-4-(dimethylamino)but-2-enoic acid (53 mg, 0.41mmol) and EDCI (103 mg, 0.542 mmol) was added pyridine (15 mL). And theresulting mixture was stirred at 20° C. for 20 h. A red solution wasformed. LCMS (Rt=3.011 min; MS Calc'd: 702.84; MS Found: 703.3 [M+H]⁺).The reaction mixture was concentrated under reduced pressure to afford ared solid. The crude product was purified by prep-HPLC (0.05% NH₃.H₂O asan additive) and lyophilized to afford a yellow solid. Then the solidwas purified by prep-HPLC (0.05% HCl as an additive) and lyophilized togive(E)-1-(4-(dimethylamino)but-2-enoyl)-N-(3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)piperidine-4-carboxamide(5.71 mg, yield: 3%) as a yellow solid.

LCMS (Shimadzu LCMS 2010, mobile phase: C) 10 mM NH₄HCO₃ in Water; D)MeCN. Gradient: 1% D increase to 5% D within 0.6 min; 5% DB increase to100% D within 3.4 min; then back to 1% D within 0.3 min. Flow rate 0.8mL/min) purity is 100%, Rt=2.499 min; MS Calc'd.: 702.3, MS Found: 703.5[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.46-1.56 (2H, m), 1.81-1.84 (2H,m), 2.63-2.67 (1H, m), 2.73 (3H, s) 2.74 (3H, s), 2.77 (2H, t, J=7.6Hz), 2.90 (2H, t, J=7.2 Hz), 2.95 (3H, s), 2.99 (3H, s), 3.10 (2H, t,J=11.6 Hz), 3.93 (1H, d, J=12.4 Hz), 4.00 (2H, t, J=5.6 Hz), 4.40 (1H,d, J=12.4 Hz), 6.12-6.18 (1H, m), 6.70 (1H, d, J=12 Hz), 6.94 (1H, d,J=6.8 Hz), 7.14 (1H, d, J=2.2 Hz), 7.20 (1H, t, J=8 Hz), 7.42 (1H, d,J=8.8 Hz), 7.49 (2H, d, J=8 Hz), 7.57 (1H, s), 7.74 (2H, d, J=7.6 Hz),7.89 (1H, d, J=8.8 Hz), 8.13 (1H, dd, J=8.8, 2 Hz), 8.28 (1H, dd, J=8.8,2.4 Hz), 8.51 (1H, d, J=2.4 Hz), 8.93 (1H, d, J=1.6 Hz), 10.07 (1H, s),10.39 (1H, br s), 10.74 (1H, br s), 11.57 (1H, br s).

Example 111:4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of tert-butyl(6-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-6-oxohexyl)carbamate

To a mixture of4-(6-((5-(3-(3-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(209 mg, 0.333 mmol) 6-((tert-butoxycarbonyl)amino)hexanoic acid (77 mg,0.33 mmol) and EDCI (96 mg, 0.50 mmol) was added pyridine (10 mL), andthen stirred at 20° C. for 20 h. A red mixture was formed. LCMS(Rt=0.659 min; MS Calc'd: 693.8; MS Found: 694.6[M+H]⁺). The solvent wasremoved under reduced pressure to afford a red solid. DCM (15 mL) andwater (15 mL) was added to the solid. The water layer was washed by DCM(30 mL×4). The organic layer was collected and concentrated to givetert-butyl(6-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-6-oxohexyl)carbamate(245 mg, yield: 79%) as a red solid. Used in the next step withoutpurification.

Step 2: Preparation of4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of tert-butyl(6-((3-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)amino)-6-oxohexyl)carbamate(245 mg, 0.353 mmol) and aq. HCl (4 M, 20 mL) was stirred at 20° C. for2 h. And the red solution was formed. LCMS (Rt=0.548 min; MS Calc'd:593.3; MS Found: 594.3 [M+H]⁺). The reaction solution was concentratedto give4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(243 mg, yield: 93%) as a red solid. Used in the next step withoutpurification. The crude product (43 mg) was purified by prep-HPLC (0.05%HCl as an additive) and lyophilized to give4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.22 mg) as a yellow solid. LCMS (Shimadzu LCMS 2010, Mobile phase:from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20% [water+0.04%TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under this condition for0.9 min, finally changed to 90% [water+0.04% TFA] and 10% [MeCN+0.02%TFA] and under this condition for 0.75 min.) purity is 96.80%, Rt=1.214min; MS Calc'd.: 593.3; MS Found: 594.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 1.29-1.36 (2H, m), 1.52-1.62 (4H, m), 2.66-2.79 (8H, m), 2.96(3H, s), 2.96 (3H, s), 6.93 (1H, d, J=7.2 Hz), 7.04 (1H, d, J=8.0 Hz),7.19 (1H, t, J=7.6 Hz), 7.42 (1H, d, J=2.2 Hz), 7.49 (2H, d, J=8.4 Hz),7.52 (1H, br s), 7.74 (2H, d, J=8.4 Hz), 7.83 (3H, br s), 7.94 (1H, d,J=9.2 Hz), 8.07 (1H, d, J=11.6 Hz), 8.20 (1H, d, J=8.8 Hz), 8.22 (1H, d,J=1.6 Hz), 8.81 (1H, br s), 9.92 (2H, br s), 11.03 (1H, br s).

Example 112:(E)-4-(6-((5-(3-(3-(6-(4-(dimethylamino)but-2-enamido)hexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of4-(6-((5-(3-(3-(6-aminohexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(200 mg, 0.270 mmol) (E)-4-(dimethylamino)but-2-enoic acid (52 mg, 0.41mmol) and EDCI (104 mg, 0.540 mmol) was added pyridine (4 mL). And theresulting mixture was stirred at 20° C. for 20 h. A red solution wasformed. LCMS (Rt=3.162 min; MS Calc'd: 704.3; MS Found: 705.2 [M+H]⁺).The solvent was concentrated to give a red solid. The crude product waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized togive(E)-4-(6-((5-(3-(3-(6-(4-(dimethylamino)but-2-enamido)hexanamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(22.96 mg, yield: 12%) as a brown solid. LCMS (Shimadzu LCMS 2010,mobile phase: C) 10 mM NH₄HCO₃ in Water; D) MeCN. Gradient: 1% Dincrease to 5% D within 0.6 min; 5% DB increase to 100% D within 3.4min; then back to 1% D within 0.3 min. Flow rate 0.8 mL/min) purity is100%, Rt=2.531 min; MS Calc'd.: 704.4, MS Found: 705.5 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 1.26-1.33 (2H, m), 1.40-1.47 (2H, m), 1.55-1.62(2H, m), 2.12 (6H, s), 2.29 (2H, t, J=7.6 Hz), 2.66 (2H, d, J=7.6 Hz),2.86 (2H, t, J=7.6 Hz), 2.98 (6H, s), 3.04-3.44 (2H, m), 3.37-3.40 (2H,m), 5.84 (1H, dt, J=12.0, 1.6 Hz), 5.93-5.99 (1H, m), 6.92-6.92 (2H, m),7.19 (1H, t, J=8.0 Hz), 7.42 (1H, d, J=8.0 Hz), 7.47-7.49 (3H, m), 7.71(2H, d, J=2.1 Hz). 7.96 (1H, dd, J=8.4, 2.4 Hz), 8.02-8.08 (2H, m), 8.10(1H, dd, J=6.4, 2.8 Hz), 8.55 (1H, J=2.8 Hz), 8.6 (1H, J=2.8 Hz), 9.32(1H, br s), 9.82 (1H, br s), 10.35 (1H, br s).

Example 113:4-(6-((5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of tert-butyl(2-(2-(3-((3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate

2,2-Dimethyl-4-oxo-3,8,11-trioxa-5-azatetradecan-14-oic acid (100 mg,0.361 mmol) and4-(6-((5-(3-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(163 mg, 361 μmol) in pyridine (6 mL) was added EDCI (104 mg, 0.541mmol). The mixture was stirred at 20° C. for 18 h. The color of solutionbecame tangerine gradually. Crude LCMS showed the purity of desiredproduct (Rt=0.628 min; MS Calc'd: 711.3; MS Found: 712.6 [M+H]⁺).Pyridine was removed under reduced pressure. After addition of DCM (30mL) to the residue, the mixture was washed with H₂O (10 mL×3). Theorganic layer was dried over Na₂SO₄, filtered and concentrated to givetert-butyl(2-(2-(3-((3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate(250 mg, yield: 97%) as a yellow solid. Used in the next step withoutfurther purification.

Step 2: Preparation of4-(6-((5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a stirred solution of tert-butyl(2-(2-(3-((3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)amino)-3-oxopropoxy)ethoxy)ethyl)carbamate(250 mg, 0.351 mmol) in DCM (4 mL) was added HCl/EtOAc (4 M, 4 mL) at20° C. A red solution turned to suspension, the reaction mixture wasstirred for 1 hour. LCMS is 49% (Rt=0.661 min; MS Calc'd: 611.3; MSFound: 612.6 [M+H]⁺). The mixture was concentrated to give4-(6-((5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(227 mg, yield: 100%) as an off-white solid. Used in the next stepwithout further purification. This product (10 mg) was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to give4-(6-((5-(3-(3-(2-(2-aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.75 mg) as a white solid. LCMS (Shimadzu LCMS 2010, mobile phase: from100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05% NH₃.H₂O] and95% [MeCN] in 5.8 min, then under this condition for 1.1 min, finallychanged to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] and under thiscondition for 0.09 min.) purity is 98.23%, Rt=3.091 min; MS Calc'd.:611.3, MS Found: 612.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.59 (4H, t,J=6.0 Hz), 2.64-2.69 (2H, m), 2.97 (3H, s), 3.01 (3H, s), 3.45-3.57 (4H,m), 3.72 (2H, t, J=6.0 Hz), 7.01 (1H, d, J=8.4 Hz), 7.44-7.51 (3H, m),7.66 (1H, d, J=7.2 Hz), 7.73 (2H, d, J=8.0 Hz), 7.84 (1H, d, J=7.6 Hz),8.01 (1H, dd, J=8.4, 2.4 Hz), 8.16 (1H, s), 8.48 (1H, t, J=2.0 Hz), 8.58(1H, d, J=2.0 Hz), 8.68 (1H, t, J=2.0 Hz), 8.72 (1H, d, J=2.0 Hz), 9.52(1H, br s), 10.21 (1H, br s), 10.48 (1H, br s).

Example 114:(E)-N,N-dimethyl-4-(6-((5-(3-(2-methyl-6-oxo-10,13-dioxa-2,7-diazahexadec-4-en-16-amido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

4-(6-((5-(3-(3-(2-(2-Aminoethoxy)ethoxy)propanamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(100 mg, 0.154 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (20 mg,0.15 mmol) in pyridine (4 mL) was added EDCI (44 mg, 0.23 mmol). Themixture was stirred at 20° C. for 18 h. A tangerine solution was formedgradually. Crude LCMS showed the purity of desired product (Rt=0.661min; MS Calc'd: 722.4; MS Found: 723.5 [M+H]⁺). Pyridine was removedunder reduced pressure. The residue was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) and lyophilized to give(E)-N,N-dimethyl-4-(6-((5-(3-(2-methyl-6-oxo-10,13-dioxa-2,7-diazahexadec-4-en-16-amido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(24.8 mg, yield: 22%) as an off-white solid. LCMS (Shimadzu LCMS 2010,mobile phase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5%[water+0.05% NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under thiscondition for 1.1 min, finally changed to 100% [water+0.05% NH₃.H₂O] and0% [MeCN] and under this condition for 0.09 min.) purity is 96.31%,Rt=1.205 min; MS Calc'd.: 722.3, MS Found: 723.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.10 (6H, s), 2.59 (2H, t, J=6.0 Hz), 2.97 (3H, s), 2.99(3H, s), 3.17-3.25 (2H, m), 3.38-3.45 (4H, m), 3.49-3.55 (4H, m), 3.72(2H, t, J=6.0 Hz), 5.85 (1H, d, J=12.0 Hz), 5.92-5.99 (1H, m), 7.01 (1H,d, J=8.0 Hz), 7.45-7.51 (3H, m), 7.66 (1H, d, J=8.0 Hz), 7.73 (2H, d,J=8.4 Hz), 7.85 (1H, d, J=7.2 Hz), 8.01 (1H, dd, J=8.8, 2.8 Hz),8.14-8.21 (2H, m), 8.48 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.4 Hz), 8.68(1H, t, J=2.0 Hz), 8.72 (1H, d, J=2.4 Hz), 8.51 (1H, br s), 10.19 (1H,br s), 10.46 (1H, br s).

Example 115:4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of 4-bromo-N,N-dimethylbenzamide

A mixture of 4-bromobenzoic acid (50.0 g, 249 mmol) in SOCl₂ (220 mL)was heated at 80° C. for 12 h under N₂ atmosphere. A yellow solution wasformed. After cooling, the reaction mixture was concentrated underreduced pressure. Then to the mixture was added DCM (500 mL),dimethylamine hydrochloride (36.0 g, 444 mmol) and TEA (207 mL), andstirred at 25° C. for 24 h under N₂. A yellow suspension was formed. TLCshowed the reaction was completed. The residue was poured into water (20mL) and extracted with DCM (20 mL×3). The combined organic layer waswashed with water (100 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuum. The residue was recrystallization by MTBE toafford 4-bromo-N,N-dimethylbenzamide (50 g, yield: 88%) as alight redsolid. ¹H NMR (400 MHz, CDCl₃) δ 2.96 (3H, s), 3.09 (3H, s), 7.29 (2H,d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz).

Step 2: Preparation ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide

A mixture of 4-bromo-N,N-dimethylbenzamide (25.0 g, 110 mmol), B₂Pin₂(36.2 g, 142 mmol), KOAc (32.3 g, 329 mmol) and Pd(dppf)Cl₂ (2.00 g,2.73 mmol) in dioxane (200 mL) was stirred at 110° C. for 14 h under N₂atmosphere. The red suspension turned to black. Crude LCMS (Rt=0.657min; MS Calc'd: 275.1; MS Found: 275.9 [M+H]⁺). The reaction mixture wasdiluted with EtOAc (200 mL), filtered and concentrated to give crudeN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(50.0 g, crude) as black oil and directly used to next step.

Step 3: Preparation of 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide

A mixture ofN,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide(15.0 g, 54.5 mmol), 5-bromopyridin-2-amine (7.86 g, 45.4 mmol), Na₂CO₃(2 M, 68 mL) in water and Pd(dppf)Cl₂ (1.33 g, 1.82 mmol) in DME (200mL) was stirred at 100° C. for 16 h under N₂ atmosphere. A blacksuspension was formed. Crude LCMS (Rt=0.427 min; MS Calc'd: 241.1; MSFound: 242.0 [M+H]⁺). The reaction mixture was diluted with ethylacetate (100 mL), dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by Combi Flash (EtOAc) to afford4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (5.0 g, yield: 46% overtwo steps) as an off white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.03 (3H,s), δ 3.12 (3H, s), 4.58 (2H, br s), 6.58 (1H, dd, J=8.4, 0.8 Hz), 7.47(2H, d, J=8.8 Hz), 7.53 (2H, d, J=8.0 Hz), 7.66 (1H, dd, J=8.4, 2.4 Hz),8.29 (1H, dd, J=2.4, 0.8 Hz).

Step 4: Preparation of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of Pd₂(dba)₃ (19 mg, 0.021 mmol) and Brettphos (22 mg, 0.041mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.4-(6-Aminopyridin-3-yl)-N,N-dimethylbenzamide (100 mg, 0.414 mmol),5-bromopyridin-3-amine (72 mg, 0.414 mmol) in dioxane (8 mL) and Cs₂CO₃(270 mg, 0.829 mmol) were added and the resulting mixture was stirred at100° C. for 16 h. A black brown mixture was formed. LCMS showed thepurity of the desired product (Rt=0.529 min; MS Calc'd: 333.2; MS Found:333.7 [M+H]⁺). The reaction mixture was diluted with DCM (10 mL),filtered and concentrated. The residue was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) and lyophilized to give4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(26.4 mg, yield: 19%) as an off-white solid. LCMS (Shimadzu LCMS 2010,mobile phase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5%[water+0.05% NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under thiscondition for 1.1 min, finally changed to 100% [water+0.05% NH₃.H₂O] and0% [MeCN] and under this condition for 0.09 min.) purity is 99.71%,Rt=2.089 min; MS Calc'd.: 333.2, MS Found: 334.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.96 (3H, s), 2.97 (3H, s), 5.22 (2H, br s), 6.92 (1H,d, J=8.8 Hz), 7.46 (2H, d, J=8.4 Hz), 7.48-7.60 (2H, m), 7.69 (2H, d,J=8.0 Hz), 7.92 (1H, dd, J=8.8, 2.4 Hz), 7.96 (1H, d, J=2.8 Hz), 8.50(1H, d, J=2.4 Hz), 9.10 (1H, br s).

Example 116:4-(6-((5-(4-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of 4-((tert-butoxycarbonyl)amino)benzoic acid

To a solution of 4-aminobenzoic acid (8.00 g, 58.3 mmol), TEA (16 mL,117 mmol), H₂O (60 mL) in dioxane (120 mL) was added Boc₂O (20.1 mL,87.5 mmol) at 10° C. Reaction mixture was allowed to stir at 10° C. for18 h. The solution became colorless to light yellow. TLC showed absenceof starting material. 1-4-dioxane was removed under reduced pressure andHCl (60 mL, 3 M) was added dropwise. White precipitate was filtered out,washed with hexane (50 mL×3) and dried to afford4-((tert-butoxycarbonyl)amino)benzoic acid (13.0 g, crude) as a whitesolid. ¹H NMR (400 MHz, CDCl₃) δ 1.53 (9H, s), 6.84 (1H, br s), 7.46(2H, d, J=8.4 Hz), 8.03 (2H, d, J=8.4 Hz).

Step 2: Preparation of tert-butyl(4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate

4-((Tert-butoxycarbonyl)amino)benzoic acid (178 mg, 0.750 mmol) and4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(250 mg, 0.750 mmol) in pyridine (4 mL) was added EDCI (216 mg, 1.12mmol). The mixture was stirred at 20° C. for 18 h. The color of solutionbecame orange gradually. Crude LCMS showed the purity of desired product(Rt=0.630 min; MS Calc'd: 552.3; MS Found: 553.4 [M+H]⁺). Pyridine wasremoved under reduced pressure. The mixture was concentrated in vacuum.The residue was purified by Combi Flash (1% TEtOAc in DCM) to givetert-butyl(4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate(260 mg, yield: 63%) as an off-white solid.

Step 3: Preparation of4-(6-((5-(4-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a stirred solution of tert-butyl(4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)phenyl)carbamate(260 mg, 0.470 mmol) in dioxane (4 mL) was added HCl/dioxane (4 M, 9.4mL) at 10° C. Then the reaction mixture was stirred at 10° C. for 16 h.A yellow solution was formed. LCMS the purity of the desired product(Rt=0.558 min; MS Calc'd: 452.2; MS Found: 453.1 [M+H]⁺). The mixturewas concentrated to afford4-(6-((5-(4-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(400 mg, crude) as an off-white solid. The residue (200 mg, crude) waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized toafford4-(6-((5-(4-aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.16 mg yield: 2%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 100%, Rt=2.526 min; MSCalc'd.: 452.2, MS Found: 453.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.97(3H, s), 2.99 (3H, s), 5.81 (2H, br s), 6.61 (2H, d, J=8.8 Hz), 6.99(1H, d, J=9.2 Hz), 7.48 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.75(2H, d, J=8.4 Hz), 7.99 (1H, dd, J=8.8, 2.8 Hz), 8.46 (1H, d, J=2.4 Hz),8.58 (1H, d, J=2.4 Hz), 8.62 (1H, t, J=2.4 Hz), 8.67 (1H, d, J=2.4 Hz),9.44 (1H, br s), 9.93 (1H, br s).

Example 117:(E)-4-(6-((5-(4-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-((5-(4-Aminobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(200 mg, 0.442 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (86 mg,0.66 mmol) in pyridine (4 mL) was added EDCI (127 mg, 0.663 mmol). Themixture was stirred at 10° C. for 18 h. A dark red solution was formedgradually. LCMS showed the purity of desired product (Rt=0.545 min; MSCalc'd: 563.3; MS Found: 564.4 [M+H]⁺). Pyridine was removed underreduced pressure. The crude product was purified by prep-HPLC (0.05%NH₃H₂O as an additive) and lyophilized to give(E)-4-(6-((5-(4-(4-(dimethylamino)but-2-enamido)benzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(12.2 mg, yield: 5%) as an off-white solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is98.29%, Rt=1.464 min; MS Calc'd.: 563.3; MS Found: 564.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.20 (6H, s), 2.98 (3H, s), 3.00 (3H, s), 3.09 (2H,d, J=5.2 Hz), 6.33 (1H, d, J=15.6 Hz), 6.80 (1H, d, J=15.6 Hz), 7.01(1H, d, J=8.8 Hz), 7.49 (2H, d, J=8.0 Hz), 7.74 (2H, d, J=8.0 Hz), 7.82(2H, d, J=8.0 Hz), 7.99 (2H, d, J=8.0 Hz), 8.03 (1H, d, J=2.8 Hz), 8.50(1H, d, J=2.0 Hz), 8.60 (1H, d, J=2.0 Hz), 8.69 (1H, t, J=2.0 Hz), 8.71(1H, d, J=2.4 Hz), 9.51 (1H, br s), 10.33 (1H, br s), 10.39 (1H, br s).

Example 118:4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of 3-(4-((tert-butoxycarbonyl)amino)phenyl)propanoicacid

To a solution of 3-(4-aminophenyl)propanoic acid (1.00 g, 6.05 mmol),TEA (1.68 mL, 12.1 mmol), H₂O (7 mL) in dioxane (14 mL) was added Boc₂O(2.08 mL, 9.07 mmol) at 10° C. Reaction mixture was allowed to stir at10° C. for 18 h. The solution turned colorless to light yellow. LCMSshowed the purity of desired product (Rt=0.641 min; MS Calc'd: 265.1; MSFound: 287.9 [M+Na]⁺). 1-4-dioxane was removed under reduced pressure.HCl (3 M) was added to adjust PH to 5. The residue was washed withpentane (50 mL×3) and dried to afford3-(4-((tert-butoxycarbonyl)amino)phenyl)propanoic acid (1.5 g, yield:93%) as an off white solid. ¹H NMR (400 MHz, CDCl₃) δ 1.51 (9H, s), 2.64(2H, t, J=8.0 Hz), 2.91 (2H, t, J=7.6 Hz), 6.50 (1H, br s), 7.12 (2H, d,J=8.0 Hz), 7.27 (2H, d, J=8.0 Hz).

Step 2: Preparation of tert-butyl(4-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate

3-(4-((Tert-butoxycarbonyl)amino)phenyl)propanoic acid (199 mg, 0.750mmol) and4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(250 mg, 0.750 mmol) in pyridine (4 mL) was added EDCI (216 mg, 1.12mmol). The mixture was stirred at 20° C. for 18 h. The color of solutionbecame orange gradually. Crude LCMS showed the purity of desired product(Rt=0.630 min; MS Calc'd: 580.3; MS Found: 581.4 [M+H]⁺). Pyridine wasremoved under reduced pressure. The mixture was concentrated in vacuum.The residue was purified by Combi Flash (1% TEtOAc in EtOAc) to givetert-butyl(4-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate(250 mg, yield: 57%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.45 (9H, s), 2.62 (2H, t, J=8.0 Hz), 2.85 (2H, t, J=8.0 Hz), 3.05 (3H,s), 3.07 (3H, s), 6.99 (1H, d, J=8.8 Hz), 7.13 (2H, d, J=8.4 Hz), 7.35(2H, d, J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.72 (2H, d, J=8.4 Hz), 7.98(1H, dd, J=8.8, 2.8 Hz), 8.32 (1H, d, J=2.0 Hz), 8.48 (1H, t, J=2.0 Hz),8.56 (1H, d, J=2.0 Hz), 8.66 (1H, d, J=2.0 Hz), 9.23 (1H, br s), 9.49(1H, br s), 10.12 (1H, br s).

Step 3: Preparation of4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a stirred solution of tert-butyl(4-(3-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)-3-oxopropyl)phenyl)carbamate(250 mg, 0.431 mmol) in dioxane (4 mL) was added HCl/dioxane (4 M, 8.6mL) at 15° C. Then the reaction mixture was stirred at 15° C. for 16 h.A yellow solution was formed. LCMS (Rt=0.539 min; MS Calc'd: 480.2; MSFound: 481.3 [M+H]⁺). The mixture was concentrated to afford4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(350 mg, crude) as an off-white solid. The residue (200 mg, crude) waspurified by prep-HPLC (0.225% FA as an additive) and lyophilized toafford4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(2.05 mg yield: 2%) as a white solid. LCMS (Shimadzu LCMS 2010, mobilephase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] to 5% [water+0.05%NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under this condition for 1.1min, finally changed to 100% [water+0.05% NH₃.H₂O] and 0% [MeCN] andunder this condition for 0.09 min.) purity is 99.11%, Rt=2.610 min; MSCalc'd.: 480.2, MS Found: 481.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.69(2H, t, J=7.6 Hz), 2.91 (2H, t, J=7.6 Hz), 2.97 (3H, s), 2.99 (3H, s),7.02 (2H, d, J=8.8 Hz), 7.06 (1H, s), 7.25 (2H, d, J=7.6 Hz), 7.49 (2H,d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 8.05 (1H, dd, J=8.4, 2.0 Hz), 8.46(1H, s), 8.58-8.61 (2H, m), 8.85 (1H, s), 9.81 (1H, br s), 10.40 (1H, brs).

Example 119:(E)-4-(6-((5-(3-(4-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

4-(6-((5-(3-(4-aminophenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(150 mg, 0.312 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (60 mg,0.66 mmol) in pyridine (4 mL) was added EDCI (90 mg, 0.468 mmol). Themixture was stirred at 10° C. for 18 h. A dark red solution was formedgradually. LCMS showed the purity of desired product (Rt=0.546 min; MSCalc'd: 591.3; MS Found: 592.5 [M+H]⁺). Pyridine was removed underreduced pressure. The crude product was purified by prep-HPLC (0.05%NH₃H₂O as an additive) and lyophilized to give(E)-4-(6-((5-(3-(4-(4-(dimethylamino)but-2-enamido)phenyl)propanamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(10.0 mg, yield: 5%) as a red solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is98.49%, Rt=1.472 min; MS Calc'd.: 591.3; MS Found: 592.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.17 (6H, s), 2.61-2.68 (2H, m), 2.89 (2H, t, J=7.6Hz), 2.98 (3H, s), 3.00 (3H, s), 3.04 (2H, d, J=4.8 Hz), 6.25 (1H, d,J=15.2 Hz), 6.66-6.74 (1H, m), 6.98 (1H, d, J=8.4 Hz), 7.21 (2H, d,J=8.8 Hz), 7.49 (2H, d, J=8.8 Hz), 7.57 (2H, d, J=8.4 Hz), 7.74 (2H, d,J=8.4 Hz), 8.00 (1H, dd, J=8.8, 2.4 Hz), 8.32 (1H, d, J=2.0 Hz), 8.50(1H, t, J=2.4 Hz), 8.57 (1H, d, J=2.8 Hz), 8.66 (1H, d, J=2.0 Hz), 9.47(1H, br s), 10.00 (1H, br s), 10.10 (1H, br s).

Example 120:methyl(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamate

To a suspension of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in anhydrous DCM (2 mL) was added a solution of methylcarbonochloridate (16 mg, 0.16 mmol) in DCM (1 mL) from 10-15° C. Thenthe reaction mixture was stirred at 10-15° C. for 1 hr. The reactionmixture turned into brown solution from suspension. LCMS is (Rt=0.661min; MS Calc'd: 391.2; MS Found: 392.0 [M+H]⁺). To the reaction mixturewas added saturated aqueous NaHCO₃ (20 mL), then extracted with DCM (20mL×2). The combined organic layer was washed with brine (20 mL), driedover anhydrous Na₂SO₄ and concentrated. The crude product was purifiedby prep-HPLC (0.225% FA as an additive). Most of the solvent was removedunder reduced pressure and the remaining part was lyophilized to givemethyl(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamate(20.6 mg, yield: 35%) as a yellow solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 98.27%, Rt=2.072 min; MS Calc'd.: 391.2, MS Found: 392.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95-3.05 (6H, m), 3.73 (3H, s),7.03 (1H, d, J=8.8 Hz), 7.50 (2H, d, J=7.6 Hz), 7.75 (2H, d, J=8.4 Hz),8.05 (1H, d, J=7.6 Hz), 8.33 (1H, s), 8.46 (1H, s), 8.61 (1H, s), 8.90(1H, s), 9.84 (1H, br s), 10.19 (1H, br s).

Example 121:4-(6-((5-benzamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), benzoic acid (27 mg, 0.22 mmol) and EDC.HCl (58 mg, 0.30mmol) in pyridine (2 mL) was stirred at 50° C. for 2 h. A brownsuspension was obtained. LCMS (Rt=0.813 min; MS Calc'd: 437.2; MS Found:438.0 [M+H]⁺). The reaction mixture was concentrated and the crudeproduct was triturated with MeOH (5 mL) and filtered. The solid waslyophilized to give4-(6-((5-benzamidopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(34.2 mg, yield: 52%) as a pale yellow solid. LCMS (Agilent LCMS1200-6140A, mobile phase: from 100% [water+0.05% NH₃.H₂O] and 0% [MeCN]to 5% [water+0.05% NH₃.H₂O] and 95% [MeCN] in 5.8 min, then under thiscondition for 1.1 min, finally changed to 100% [water+0.05% NH₃.H₂O] and0% [MeCN] and under this condition for 0.09 min.) purity is 97.22%,Rt=2.849 min; MS Calc'd.: 437.2, MS Found: 438.2 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 2.95-3.05 (6H, m), 7.01 (1H, d, J=8.8 Hz), 7.49 (2H, d,J=8.4 Hz), 7.55-7.65 (3H, m), 7.74 (2H, d, J=8.4 Hz), 7.90-8.05 (3H, m),8.51 (1H, d, J=2.0 Hz), 8.59 (1H, s), 8.70 (1H, s), 8.73 (1H, d, J=2.4Hz), 9.51 (1H, br s), 10.45 (1H, br s).

Example 122:4-(6-((5-(2-cyanoacetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A solution of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), 2-cyanoacetic acid (19 mg, 0.22 mmol) and EDC.HCl (58mg, 0.30 mmol) in pyridine (2 mL) was stirred at 50° C. for 2 h. A brownsuspension was formed. LCMS (Rt=0.668 min; MS Calc'd: 400.2; MS Found:401.0 [M+H]⁺). The reaction mixture was filtered and the solid waswashed with MeOH (2 mL×2), then lyophilized to give4-(6-((5-(2-cyanoacetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(10.3 mg, yield: 17%) as a yellow solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 100%, Rt=2.051 min; MS Calc'd.: 400.2, MS Found: 401.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95-3.05 (6H, m), 3.97 (2H, s),7.00 (1H, d, J=8.8 Hz), 7.49 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz),8.01 (1H, dd, J=8.8, 2.8 Hz), 8.32 (1H, s), 8.54 (1H, d, J=2.0 Hz), 8.58(1H, d, J=2.4 Hz), 8.66 (1H, d, J=2.4 Hz), 9.54 (1H, br s), 10.50 (1H,br s).

Example 123:N,N-dimethyl-4-(6-((5-(2-phenylacetamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

A mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), 2-phenylacetic acid (31 mg, 0.22 mmol) and EDC.HCl (58mg, 0.30 mmol) in pyridine (2 mL) was stirred at 50° C. for 2 h. LCMS(Rt=0.832 min; MS Calc'd: 451.2; MS Found: 452.1 [M+H]⁺). The reactionmixture was concentrated to give the crude product, which was trituratedwith MeOH (3 mL) and filtered. LCMS indicated it still contains someimpurity. Then it was combined with the filtrate and further purified byprep-HPLC (0.225% FA as an additive). Most of MeCN was removed underreduced pressure and the remaining part was lyophilized to giveN,N-dimethyl-4-(6-((5-(2-phenylacetamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(22.3 mg, yield: 33%) as a pale yellow solid. LCMS (Agilent LCMS1200-6140A, mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA]to 95% [water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to100% [MeCN+0.1% FA] under this condition for 3.4 min, finally back to99% [water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for0.5 min.) purity is 99.00%, Rt=2.376 min; MS Calc'd.: 451.2, MS Found:452.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95-3.05 (6H, m), 3.72 (2H,s), 7.01 (1H, d, J=8.8 Hz), 7.25-7.40 (5H, m), 7.49 (2H, d, J=8.0 Hz),7.74 (2H, d, J=8.4 Hz), 8.02 (1H, dd, J=8.4, 2.0 Hz), 8.44 (1H, s),8.55-8.60 (2H, m), 8.74 (1H, s), 9.65 (1H, br s), 10.53 (1H, br s).

Example 124:N,N-dimethyl-4-(6-((5-(3-methylureido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

Step 1: Preparation of 1-(5-bromopyridin-3-yl)-3-methylurea

To a solution of 5-bromopyridin-3-amine (1.00 g, 5.78 mmol) in pyridine(10 mL) was added methylcarbamic chloride (649 mg, 6.94 mmol) between10-15° C. Then the reaction mixture was stirred at 10-15° C. for 3 h.The reaction mixture turned into red from yellow solution. LCMS(Rt=0.555 min; MS Calc'd: 229.0; MS Found: 230.0 [M+H]⁺). The reactionmixture was diluted with EtOAc (100 mL), then washed with 1N aqueous HCl(25 mL×2), saturated aqueous NaHCO₃ (50 mL), brine (25 mL) andconcentrated. The crude product was triturated with MTBE (5 mL) andwashed with MTBE (2 mL×2) to give 1-(5-bromopyridin-3-yl)-3-methylurea(520 mg, yield: 39%) as a pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.60-2.70 (3H, m), 6.29 (1H, br s), 8.20 (1H, t, J=2.4 Hz), 8.26 (1H, t,J=2.4 Hz), 8.43 (1H, d, J=2.4 Hz), 8.96 (1H, br s).

Step 2: Preparation ofN,N-dimethyl-4-(6-((5-(3-methylureido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

A mixture of 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (100 mg, 0.41mmol), 1-(5-bromopyridin-3-yl)-3-methylurea (114 mg, 0.50 mmol),Pd₂(dba)₃ (19 mg, 0.021 mmol), Brettphos (22 mg, 0.041 mmol) and Cs₂CO₃(270 mg, 0.83 mmol) in anhydrous dioxane (3 mL) was degassed and purgedwith N₂ for 3 times. Then the resulting reaction mixture was heated at100° C. for 16 h under N₂ atmosphere. The reaction mixture turned intoyellow suspension from red. Crude LCMS showed the purity of desiredproduct is 63% (Rt=0.630 min; MS Calc'd: 390.2; MS Found: 391.1 [M+H]⁺).To the mixture was added water (25 mL), then extracted with EtOAc/THF(25 mL×3, 1/1). The combined organic layer was washed with brine (25mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by prep-HPLC (0.225% FA as an additive). Most of MeCN wasremoved under reduced pressure and the remaining part was lyophilized togiveN,N-dimethyl-4-(6-((5-(3-methylureido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(51.0 mg, yield: 32%) as a yellow solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 100%, Rt=1.974 min; MS Calc'd.: 390.2, MS Found: 391.4[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.68 (3H, d, J=4.8 Hz), 2.95-3.05(6H, m), 6.34 (1H, q, J=4.8 Hz), 7.01 (1H, d, J=8.8 Hz), 7.49 (2H, d,J=8.0 Hz), 7.74 (2H, d, J=8.4 Hz), 8.02 (1H, dd, J=8.8, 2.0 Hz), 8.32(1H, s), 8.37 (1H, s), 8.58 (1H, d, J=2.0 Hz), 8.70 (1H, s), 9.04 (1H,br s), 9.65 (1H, br s).

Example 125:4-(6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

A mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), N,N-dimethylglycine (23 mg, 0.22 mmol) and EDC.HCl (58mg, 0.30 mmol) in pyridine (2 mL) was heated at 50° C. for 2 h. CrudeLCMS showed the purity of desired product (Rt=0.816 min; MS Calc'd:418.2; MS Found: 419.0 [M+H]⁺). The reaction mixture was concentratedand the residue was purified by prep-HPLC (0.225% FA as an additive).Most of MeCN was removed under reduced pressure and the remaining partwas lyophilized to give the product (42.6 mg, still contains someimpurity). The product was then further purified by pre-HPLC (hexane/IPAas eluent) and lyophilized to give4-(6-((5-(2-(dimethylamino)acetamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(9.9 mg, yield: 16%) as a white solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 100%, Rt=1.776 min; MS Calc'd.: 418.2, MS Found: 419.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.30 (6H, s), 2.95-3.05 (6H, m),3.12 (2H, s), 6.99 (1H, d, J=8.8 Hz), 7.49 (2H, d, J=8.4 Hz), 7.74 (2H,d, J=8.0 Hz), 7.99 (1H, dd, J=8.8, 2.0 Hz), 8.37 (1H, d, J=1.6 Hz), 8.55(1H, s), 8.58 (1H, d, J=1.6 Hz), 8.70 (1H, s), 9.48 (1H, br s), 9.93(1H, br s).

Example 126:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-4-carboxamide

A mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), tetrahydro-2H-pyran-4-carboxylic acid (29 mg, 0.22 mmol)and EDC.HCl (58 mg, 0.30 mmol) in pyridine (2 mL) was stirred at 50° C.for 2 h. Crude LCMS showed the purity of desired product (Rt=0.800 min;MS Calc'd: 445.2; MS Found: 446.0 [M+H]⁺). The reaction mixture wasconcentrated and the residue was purified by prep-HPLC (0.225% FA as anadditive). Most of MeCN was removed under reduced pressure and theremaining part was lyophilized to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-4-carboxamide(20.9 mg, yield: 28%) as a yellow solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 97.71%, Rt=2.082 min; MS Calc'd.: 445.2, MS Found: 446.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.80 (4H, m), 2.60-2.70 (1H,m), 2.95-3.05 (6H, m), 3.30-3.40 (2H, m), 3.90-3.95 (2H, m), 6.99 (1H,d, J=8.8 Hz), 7.49 (2H, d, J=8.4 Hz), 7.74 (2H, d, J=8.4 Hz), 8.01 (1H,dd, J=8.8, 2.0 Hz), 8.40 (1H, s), 8.55-8.60 (2H, m), 8.69 (1H, s), 9.53(1H, br s), 10.15 (1H, br s).

Example 127:N,N-dimethyl-4-(6-((5-(methylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(160 mg, 0.48 mmol) in DCM (8 mL) was added TEA (121 mg, 1.20 mmol) andMsCl (110 mg, 0.96 mmol, 0.7 mL) dropwise and stirred at 25° C. for 20 hto give a brown solution. LCMS showed the reaction was incomplete. MsCl(110 mg, 0.7 mL) was added into the above mixture and stirred foranother 16 h to give a brown suspension. LCMS (Rt=0.692 min; MS Calc'd:411.1; MS Found: 412.1 [M+H]⁺). The mixture was concentrated underreduced pressure to give a residue. The residue was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) to giveN,N-dimethyl-4-(6-((5-(methylsulfonamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(15.8 mg, yield: 8%) as an off-white solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 98.73%, Rt=1.486 min; MS Calc'd.: 411.1; MS Found:412.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.90-3.04 (9H, m), 7.48 (2H,d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.94 (1H, d, J=2.0 Hz), 7.99 (1H,dd, J=8.8, 2.4 Hz), 8.04 (1H, t, J=2.4 Hz), 8.56 (1H, d, J=2.4 Hz), 8.67(1H, d, J=2.4 Hz), 9.47 (1H, br s).

Example 128:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)picolinamide

To a mixture of picolinic acid (28 mg, 0.23 mmol) in pyridine (2 mL) wasadded EDC.HCl (43 mg, 0.225 mmol) and4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), the reaction mixture was stirred at 50° C. for 2 h togive a brown solution. LCMS (Rt=1.163 min; MS Calc'd: 438.2; MS Found:439.2 [M+H]⁺). The mixture was concentrated under reduced pressure togive a residue. The residue was purified by washing with MeOH (5 mL) togive a crude product. The crude product was further purified byprep-HPLC (0.05% NH₃.H₂O as an additive) to give an impure product (25mg, LCMS purity is 94.6%). The impure product was further purified bywashing with MeOH (5 mL) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)picolinamide(9.7 mg, yield: 15%) as a pale yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.575 min; MS Calc'd.: 438.2; MS Found:439.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.98 (6H, s), 7.01 (1H, d,J=8.4 Hz), 7.49 (2H, d, J=8.0 Hz), 7.69-7.80 (3H, m), 8.01 (1H, dd,J=8.4, 2.4 Hz), 8.10 (1H, t, J=1.2 Hz), 8.19 (1H, d, J=7.6 Hz), 8.60(2H, d, J=2.8 Hz), 8.71-8.85 (3H, m), 9.51 (1H, br s), 10.82 (1H, br s).

Example 129:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)nicotinamide

To a mixture of nicotinic acid (33 mg, 0.27 mmol) in pyridine (2 mL) wasadded EDC.HCl (52 mg, 0.27 mmol) and4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (60mg, 0.18 mmol), the resulting mixture was stirred at 50° C. for 2 h togive a brown solution. LCMS (Rt=0.690 min; MS Calc'd: 438.2; MS Found:439.1 [M+H]⁺). The mixture was concentrated under reduced pressure togive a residue. The residue was purified by washing with MeOH (5 mL).The filter cake was further purified by prep-HPLC (0.225% FA as anadditive) and lyophilized to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)nicotinamide(20.6 mg, yield: 26%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.452 min; MS Calc'd.: 438.2; MS Found:439.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.05 (6H, m), 7.03 (1H,d, J=8.4 Hz), 7.49 (2H, d, J=8.8 Hz), 7.60-7.64 (1H, m), 7.74 (2H, d,J=8.8 Hz), 8.04 (1H, dd, J=8.4, 2.4 Hz), 8.33-8.37 (1H, m), 8.60 (2H,dd, J=8.0, 2.4 Hz), 8.76-8.78 (1H, m), 8.80 (1H, dd, J=4.8, 1.6 Hz),8.85-8.88 (1H, m), 9.13-9.17 (1H, m), 9.74 (1H, br s), 10.79 (1H, br s).

Example 130:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide

To a mixture of isonicotinic acid (28 mg, 0.23 mmol) in DMF (5 mL) wasadded TEA (38 mg, 0.37 mmol) and HATU (143 mg, 0.375 mmol), the reactionmixture was stirred at 25° C. for 0.5 hour, then added4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), the resulting mixture was stirred at 25° C. for 16 h togive a saffron solution. LCMS (Rt=0.706 min; MS Calc'd: 438.2; MS Found:439.2 [M+H]⁺). The mixture was diluted with water (10 mL), thenextracted with DCM (10 mL×2), the combined extracts were washed withbrine (15 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by washingwith MeOH (5 mL). The filter cake was further purified by prep-HPLC(0.05% NH₃.H₂O as an additive) and lyophilized to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide(12.5 mg, yield: 18%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 96.50%, Rt=1.466 min; MS Calc'd.: 438.2; MS Found:439.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.05 (6H, m), 7.01 (1H,d, J=8.8 Hz), 7.49 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.85-7.96(2H, m), 8.01 (1H, dd, J=8.4, 2.4 Hz), 8.51 (1H, d, J=2.0 Hz), 8.59 (1H,d, J=2.4 Hz), 8.67-8.75 (2H, m), 8.78-8.83 (2H, m), 9.54 (1H, br s),10.69 (1H, br s).

Example 131:2-amino-N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide

To a mixture of 2-aminoisonicotinic acid (37 mg, 0.27 mmol) in pyridine(2 mL) was added EDC.HCl (69 mg, 0.36 mmol) and4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (60mg, 0.18 mmol), the resulting mixture was stirred at 50° C. for 2 h togive a saffron solution. LCMS (Rt=0.685 min; MS Calc'd: 453.2; MS Found:489.2 [M+Na]+). The mixture was concentrated under reduced pressure togive a residue. The residue was purified by washing with MeOH/water (5mL/1 mL) to give a crude product. Then further purified by prep-HPLC(0.225% FA as an additive) and lyophilized to give2-amino-N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)isonicotinamide(16.2 mg, yield: 20%) as a pale yellow powder. LCMS (Shimadzu LCMS 2010,Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 99.45%, Rt=1.386 min; MS Calc'd.: 453.2; MS Found:454.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.04 (6H, m), 6.25 (2H,br s), 6.86-6.89 (1H, m), 6.95 (1H, dd, J=5.6, 1.6 Hz), 7.00 (1H, d,J=8.8 Hz), 7.48 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 8.00 (1H, dd,J=8.8, 2.4 Hz), 8.08 (1H, d, J=5.2 Hz), 8.46 (1H, d, J=2.0 Hz), 8.58(1H, d, J=2.4 Hz), 8.66 (1H, t, J=2.0 Hz), 8.73 (1H, d, J=2.4 Hz), 9.52(1H, br s), 10.48 (1H, br s).

Example 132:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamide

Step 1: Preparation of 3-(acetoxymethyl)-4-bromobenzoic acid

To a mixture of 4-bromo-3-(hydroxymethyl)benzoic acid (300 mg, 1.30mmol) in pyridine (10 mL) was added Ac₂O (132 mg, 1.30 mmol), thereaction mixture was stirred at 25° C. for 2 h to give a yellowsolution. LCMS showed the reaction was completed. The mixture wasconcentrated under reduced pressure to remove pyridine. The mixture wasdiluted with water (10 mL). The mixture was adjust to pH=2 with HCl(2M). The mixture was extracted with EtOAc (20 mL×2). The combinedextracts were washed with brine (30 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give3-(acetoxymethyl)-4-bromobenzoic acid (320 mg, yield: 90%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.11 (3H, s), 5.16 (2H, s), 7.81-7.84(2H, m), 8.00-8.03 (1H, m).

Step 2: Preparation of2-bromo-5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(100 mg, 0.30 mmol) in pyridine (2 mL) was added3-(acetoxymethyl)-4-bromobenzoic acid (164 mg, 0.60 mmol) and EDC.HCl(115 mg, 0.60 mmol), the reaction mixture was stirred at 50° C. for 2 hto give a brown suspension. LCMS (Rt=0.626 min; MS Calc'd: 589.1; MSFound: 589.9 [M+H]⁺). The mixture was concentrated under reducedpressure to give a residue. The residue was purified by washing withMeCN/pentane (2 mL/6 mL) to give2-bromo-5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate (120 mg, yield: 68%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.13 (3H, s), 2.90-3.08 (6H, m), 5.20 (2H, s), 7.00 (1H, d,J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.87 (1H, d,J=8.4 Hz), 7.90-7.94 (1H, m), 8.01 (1H, dd, J=8.8, 2.8 Hz), 8.06 (1H, d,J=2.0 Hz), 8.49 (1H, d, J=2.0 Hz), 8.58 (1H, d, J=2.8 Hz), 8.67-8.73(2H, m), 9.53 (1H, br s), 10.57 (1H, br s).

Step 3: Preparation of5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate

To a mixture of2-bromo-5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate (120 mg, 0.20 mmol) in dioxane (10 mL) was added B₂Pin₂ (78 mg,0.30 mmol), Pd(dppf)Cl₂ (15 mg, 0.02 mmol) and KOAc (60 mg, 0.61 mmol),the reaction mixture was stirred at 100° C. under N₂ atmosphere for 16 hto give a brown suspension. LCMS (Rt=0.825 min; MS Calc'd: 635.3; MSFound: 636.3 [M+H]⁺). The mixture was diluted with water (20 mL) andextracted with EtOAc (25 mL×2). The combined extracts were washed withbrine (30 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by CombiFlashCombi Flash (DCM:MeOH=100:1 to 95:5) to give5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (100 mg, yield: 35%) as an off-white solid.

LCMS purity is 45%, Rt=0.846 min; MS Calc'd: 635.3; MS Found: 636.3[M+H]⁺).

Step 4: Preparation ofN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamide

To a mixture of5-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (100 mg, crude) in MeOH (5 mL) was added NaOH (12 mg, 0.31 mmol)in MeOH (1 mL) dropwise. The reaction mixture was stirred at 40° C. for6 h to give a brown solution. LCMS (Rt=0.677 min; MS Calc'd: 493.2; MSFound: 494.1 [M+H]⁺). The mixture was concentrated under reducedpressure to give a residue. The residue was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) purification to give an impure product. Thenfurther purified by washing with MeOH/MeCN (1 mL/4 mL) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-5-carboxamide(8.0 mg, yield: 10%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 98.92%, Rt=1.594 min; MS Calc'd.: 493.2, MS Found:494.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.92-3.06 (6H, m), 5.10 (2H,s), 7.00 (1H, d, J=8.8 Hz), 7.48 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4Hz), 7.88 (1H, d, J=8.0 Hz), 7.94 (1H, d, J=7.6 Hz), 7.97-8.05 (2H, m),8.50 (1H, d, J=2.0 Hz), 8.58 (1H, d, J=2.4 Hz), 8.70 (1H, t, J=2.4 Hz),8.73 (1H, d, J=2.4 Hz), 9.40 (1H, br s), 9.51 (1H, br s), 10.52 (1H, brs).

Example 133:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide

Step 1: Preparation of 3-bromo-4-(hydroxymethyl)benzoic acid

To a mixture of 3-bromo-4-formylbenzoic acid (300 mg, 1.31 mmol) in THF(15 mL) was added NaBH₄ (50 mg, 1.3 mmol) in portions at 0° C., thenwarmed to 20° C. and stirred for 3 h to give a black suspension. LCMSshowed the reaction was completed. The mixture was quenched with water(15 mL), then adjust to pH=1 with HCl (1M). The mixture was extractedwith EtOAc (15 mL×2). The combined extracts were washed with brine (20mL×2), dried over Na₂SO₄, filtered and concentrated under reducedpressure to give 3-bromo-4-(hydroxymethyl)benzoic acid (280 mg, yield:92%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 4.55 (2H, d, J=5.2Hz), 5.62 (1H, t, J=5.2 Hz), 7.67 (1H, d, J=7.6 Hz), 7.96 (1H, dd,J=8.0, 1.2 Hz), 8.03 (1H, d, J=1.2 Hz).

Step 2: Preparation of 4-(acetoxymethyl)-3-bromobenzoic acid

To a mixture of 3-bromo-4-(hydroxymethyl)benzoic acid (280 mg, 1.21mmol) in pyridine (10 mL) was added Ac₂O (124 mg, 1.21 mmol), thereaction mixture was stirred at 25° C. for 2 h to give a yellowsolution. LCMS showed the reaction was completed. The mixture wasconcentrated under reduced pressure to remove pyridine and then dilutedwith water (20 mL). The mixture was adjust to pH=1 with HCl (2M). Themixture was extracted with DCM (20 mL×2). The combined extracts werewashed with brine (25 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give4-(acetoxymethyl)-3-bromobenzoic acid (300 mg, yield: 91%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.13 (3H, s), 5.16 (2H, s), 7.60 (1H,d, J=8.0 Hz), 7.95 (1H, dd, J=8.0, 1.6 Hz), 8.10 (1H, d, J=1.6 Hz).

Step 3: Preparation of2-bromo-4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added4-(acetoxymethyl)-3-bromobenzoic acid (82 mg, 0.30 mmol) and EDC.HCl (57mg, 0.30 mmol), the reaction mixture was stirred at 50° C. for 2 h togive a brown suspension. LCMS (Rt=0.725 min; MS Calc'd: 589.1; MS Found:590.0 [M+H]⁺). The mixture was concentrated under reduced pressure togive a residue. The residue was purified by washing with MeOH (3 mL)twice to give2-bromo-4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate (75 mg, yield: 82%) as an off-white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 2.14 (3H, s), 2.92-3.08 (6H, m), 5.20 (2H, s), 7.01 (1H, d,J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.65 (1H, d, J=8.0 Hz), 7.73 (2H, d,J=8.4 Hz), 7.94-8.04 (2H, m), 8.27 (1H, d, J=2.0 Hz), 8.50 (1H, d, J=2.0Hz), 8.59 (1H, d, J=2.4 Hz), 8.65-8.74 (2H, m), 9.52 (1H, br s), 10.54(1H, br s).

Step 4: Preparation of4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate

To a mixture of2-bromo-4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)benzylacetate (130 mg, 0.221 mmol) in dioxane (10 mL) was added B₂Pin₂ (84 mg,0.33 mmol), Pd(dppf)Cl₂ (16 mg, 0.022 mmol) and KOAc (65 mg, 0.66 mmol),the reaction mixture was stirred at 100° C. under N₂ atmosphere for 16 hto give a brown suspension. LCMS is 63% (Rt=0.677 min; MS Calc'd: 635.3;MS Found: 636.0 [M+H]⁺). The mixture was diluted with water (15 mL) andextracted with EtOAc (20 mL×2). The combined extracts were washed withbrine (20 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (120 mg, yield: 85%) as a black gum.

Step 5: Preparation ofN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide

To a mixture of4-((5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)carbamoyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylacetate (60 mg, 0.09 mmol) in MeOH (5 mL) was added NaOH (8 mg, 0.2mmol) in MeOH (1 mL) dropwise. The reaction mixture was stirred at 40°C. for 6 h to give a brown suspension. The reaction was repeated once.LCMS (batch 1) (Rt=0.786 min; MS Calc'd: 493.2; MS Found: 494.0 [M+H]⁺).LCMS (batch 2) (Rt=0.782 min; MS Calc'd: 493.2; MS Found: 494.3 [M+H]⁺).The two batches were combined and concentrated under reduced pressurerespective to give a residue. The residue was purified by prep-HPLC(0.01% NH₄HCO₃ as an additive) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborole-6-carboxamide(30.7 mg, yield: 32%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 97.81%, Rt=1.569 min; MS Calc'd.: 493.2, MS Found:494.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.93-3.04 (6H, m), 5.09 (2H,s), 7.01 (1H, d, J=8.8 Hz), 7.48 (2H, d, J=8.4 Hz), 7.58 (1H, d, J=8.0Hz), 7.73 (2H, d, J=8.4 Hz), 8.01 (1H, dd, J=8.4, 2.4 Hz), 8.08 (1H, dd,J=8.0, 1.6 Hz), 8.36 (1H, d, J=2.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.59(1H, d, J=2.8 Hz), 8.68-8.75 (2H, m), 9.39 (1H, br s), 9.51 (1H, br s),10.51 (1H, br s).

Example 134:4-(6-((5-(3-(3-aminobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

Step 1: Preparation of 1-(5-bromopyridin-3-yl)pyrrolidin-2-one

To a mixture of pyrrolidin-2-one (4.00 g, 47.0 mmol),3,5-dibromopyridine (11.1 g, 47.0 mmol) in dioxane (120 mL) was addedCuI (895 mg, 4.70 mmol), TMEDA (546 mg, 4.70 mmol) and K₂CO₃ (9.74 g,70.50 mmol). The reaction mixture was stirred at 110° C. under N₂atmosphere for 16 h to give a blue suspension. LCMS (Rt=0.800 min; MSCalc'd: 242.0; MS Found: 242.7 [M+H]⁺). The mixture was cooled to roomtemperature. Then diluted with water (40 mL) and extracted with EtOAc(50 mL×2). The combined extracts were washed with brine (50 mL×2), driedover Na₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by Combi Flash (pentane:EtOAc=4:1 to1:1 to 1:3) to give 1-(5-bromopyridin-3-yl)pyrrolidin-2-one (0.8 g,yield: 7%) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.13(2H, m), 2.50-2.56 (2H, m), 3.88 (2H, t, J=7.2 Hz), 8.43 (1H, t, J=2.0Hz), 8.46 (1H, d, J=1.6 Hz), 8.84 (1H, d, J=2.0 Hz).

Step 2: Preparation of1-(5-bromopyridin-3-yl)-3-(3-nitrobenzyl)pyrrolidin-2-one

To a mixture of LHMDS (1 M, 2.05 mL) in THF (8 mL) was added1-(5-bromopyridin-3-yl)pyrrolidin-2-one (0.45 g, 1.9 mmol) in THF (8 mL)dropwise at −78° C. and stirred for 0.5 hour, then added1-(bromomethyl)-3-nitrobenzene (484 mg, 2.24 mmol) in THF (8 mL)dropwise at −78° C., then warmed to room temperature (20° C.) andstirred for another 16 h to give a yellow solution. LCMS (Rt=0.667 min;MS Calc'd: 375.0; MS Found: 375.8 [M+H]⁺). The mixture was quenchedsaturated NH₄Cl solution (30 mL), then extracted with EtOAc (40 mL×2),the combined extracts were washed with brine (40 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by Combi Flash (pentane:EtOAc=3:1 to1:1 to 1:3) to give1-(5-bromopyridin-3-yl)-3-(3-nitrobenzyl)pyrrolidin-2-one (200 mg,yield: 26%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.72-1.85 (1H,m), 2.04-2.13 (1H, m), 2.85-2.94 (1H, m), 3.03-3.14 (1H, m), 3.20-3.29(1H, m), 3.69-3.82 (2H, m), 7.62 (1H, t, J=8.0 Hz), 7.77 (1H, d, J=7.6Hz), 8.10 (1H, dd, J=8.0, 1.6 Hz), 8.15-8.18 (1H, m), 8.43 (1H, t, J=2.0Hz), 8.48 (1H, d, J=2.0 Hz), 8.86 (1H, d, J=2.0 Hz).

Step 3: Preparation ofN,N-dimethyl-4-(6-((5-(3-(3-nitrobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide

A mixture of Pd₂(dba)₃ (24 mg, 0.026 mmol), Brettphos (14 mg, 0.026mmol) in dioxane (2 mL) was stirred at 50° C. for 10 min. Then added1-(5-bromopyridin-3-yl)-3-(3-nitrobenzyl)pyrrolidin-2-one (100 mg, 0.27mmol), 4-(6-aminopyridin-3-yl)-N,N-dimethylbenzamide (96 mg, 0.40 mmol)and Cs₂CO₃ (173 mg, 0.53 mmol) in dioxane (3 mL). The reaction mixturewas stirred at 100° C. under N₂ atmosphere for 16 h to give a brownsuspension. LCMS (Rt=0.749 min; MS Calc'd: 536.2; MS Found: 537.1[M+H]⁺). The mixture was cooled to room temperature and filtered. Thefilter cake was washed with DCM (8 mL×2). The filtrate was concentratedunder reduced pressure to give a residue. The residue was purified byCombi Flash (DCM:MeOH=100:1 to 95:5 to 10:1) to giveN,N-dimethyl-4-(6-((5-(3-(3-nitrobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide(120 mg, yield: 43%) as a yellow solid. Crude LCMS is 51% (Rt=1.732 min;MS Calc'd: 536.2; MS Found: 537.2 [M+H]⁺).

Step 4: Preparation of4-(6-((5-(3-(3-aminobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

First Batch:

To a mixture ofN,N-dimethyl-4-(6-((5-(3-(3-nitrobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide(30 mg, 0.056 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10% purity,50% wet), the resulting mixture was purged in H₂ atmosphere for 3 times,then stirred at 20° C. under H₂ atmosphere (15 Psi) for 3 h to give ablack suspension. LCMS (Rt=0.553 min; MS Calc'd: 506.2; MS Found: 507.1[M+H]⁺). The mixture was diluted with DMF (3 mL) and filtered. Thefilter cake was washed with hot MeOH (5 mL×2). The filtrate wasconcentrated under reduced pressure to give a residue. The residue waspurified on next batch.

Second Batch: ES6958-73

To a mixture ofN,N-dimethyl-4-(6-((5-(3-(3-nitrobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)benzamide(90 mg, 0.17 mmol) in MeOH (10 mL) was added Pd/C (100 mg, 10% purity,50% wet), the resulting mixture was purged in H₂ atmosphere for 3 times,then stirred at 20° C. under H₂ atmosphere (15 Psi) for 3 h to give ablack suspension. LCMS is 64% (Rt=0.687 min; MS Calc'd: 506.2; MS Found:507.3 [M+H]⁺). The mixture was diluted with DMF (5 mL) and filtered. Thefilter cake was washed with hot MeOH (10 mL×2). The filtrate wasconcentrated under reduced pressure to give a residue. The residue andfirst batch were combined and purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and to give4-(6-((5-(3-(3-aminobenzyl)-2-oxopyrrolidin-1-yl)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(14.1 mg, average yield: 12%) as a white solid. LCMS (Shimadzu LCMS2010, Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA]and 60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9min, finally changed to 100% [water+0.04% TFA] and under this conditionfor 0.75 min) purity is 100%, Rt=1.514 min; MS Calc'd: 506.2; MS Found:507.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.68-1.77 (1H, m), 2.06-2.18(1H, m), 2.81-2.92 (1H, m), 2.92-3.06 (7H, m), 3.28-3.31 (1H, m),3.65-3.78 (2H, m), 4.98 (2H, br s), 6.35-6.43 (2H, m), 6.43-6.49 (1H,m), 6.93 (1H, t, J=7.6 Hz), 6.99 (1H, d, J=8.4 Hz), 7.48 (2H, d, J=8.0Hz), 7.74 (2H, d, J=8.4 Hz), 8.00 (1H, dd, J=8.4, 2.4 Hz), 8.40 (1H, d,J=2.0 Hz), 8.56-8.63 (2H, m), 8.78 (1H, d, J=2.0 Hz), 9.52 (1H, br s).

Example 135:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-6-carboxamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added 1H-indole-6-carboxylic acid(36 mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reaction mixturewas stirred at 50° C. for 2 h to give a brown solution. LCMS (Rt=1.189min; MS Calc'd: 476.2; MS Found: 477.2 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by washing with MeOH/water (5 mL/1 mL) to give a crude product.Then further purified by prep-HPLC (0.05% NH₃.H₂O as an additive) give aproduct (MeCN was confirmed by HNMR), then further purified by washingwith MeOH (2 mL) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-6-carboxamide(8.3 mg, yield: 11%) as a pale yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 98.28%, Rt=1.637 min; MS Calc'd.: 476.2; MS Found:477.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95-3.04 (6H, m), 6.50-6.54(1H, m), 7.01 (1H, d, J=8.4 Hz), 7.48 (2H, d, J=8.4 Hz), 7.57 (1H, t,J=2.8 Hz), 7.65-7.68 (2H, m), 7.74 (2H, d, J=8.0 Hz), 8.01 (1H, dd,J=8.4, 2.4 Hz), 8.09-8.13 (1H, m), 8.52 (1H, d, J=2.0 Hz), 8.59 (1H, d,J=2.8 Hz), 8.69-8.72 (2H, m), 9.49 (1H, br s), 10.35 (1H, br s), 11.50(1H, br s).

Example 136:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzo[d]oxazole-6-carboxamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added benzo[d]oxazole-6-carboxylicacid (37 mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reactionmixture was stirred at 50° C. for 2 h to give a brown suspension. LCMS(Rt=1.152 min; MS Calc'd: 478.2; MS Found: 479.2 [M+H]⁺). The mixturewas concentrated under reduced pressure to give a residue. The residuewas purified by washing with MeOH/water (5 mL/1 mL) to give a crudeproduct. The impure product was further purified by prep-HPLC (0.05%NH₃.H₂O as an additive) to give an impure product. Then further purifiedby washing with MeOH (2 mL) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzo[d]oxazole-6-carboxamide(5.2 mg, yield: 7%) as a white solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 98.01%, Rt=2.231 min; MS Calc'd.: 478.2; MS Found: 479.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.94-3.06 (6H, m), 7.01 (1H, d,J=8.4 Hz), 7.49 (2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.4 Hz), 7.97 (1H, d,J=8.4 Hz), 8.01 (1H, dd, J=8.4, 2.4 Hz), 8.07 (1H, dd, J=8.0, 2.0 Hz),8.44 (1H, d, J=1.2 Hz), 8.53 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.4 Hz),8.70-8.75 (2H, m), 8.95 (1H, s), 9.53 (1H, br s), 10.55 (1H, br s),

Example 137:N,N-dimethyl-4-(6-((5-(3-phenylpropanamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added 3-phenylpropanoic acid (34mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reaction mixture wasstirred at 50° C. for 2 h to give a brown solution. LCMS (Rt=0.783 min;MS Calc'd: 465.2; MS Found: 466.1 [M+H]⁺). The mixture was concentratedunder reduced pressure to give a residue. The residue was purified bywashing with MeOH/water (5 mL/1 mL) to give a crude product. Thenfurther purified by prep-HPLC (0.05% NH₃.H₂O as an additive) to giveN,N-dimethyl-4-(6-((5-(3-phenylpropanamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(33.9 mg, yield: 49%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.681 min; MS Calc'd: 465.2; MS Found:466.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.67 (2H, t, J=7.2 Hz),2.91-3.05 (8H, m), 6.98 (1H, d, J=8.8 Hz), 7.12-7.20 (1H, m), 7.21-7.35(4H, m), 7.48 (2H, d, J=8.0 Hz), 7.73 (2H, d, J=8.4 Hz), 7.99 (1H, dd,J=8.4, 2.4 Hz), 8.32 (1H, d, J=1.6 Hz), 8.50 (1H, d, J=2.0 Hz), 8.56(1H, d, J=2.4 Hz), 8.65 (1H, d, J=2.4 Hz), 9.45 (1H, br s), 10.09 (1H,br s).

Example 138:N,N-dimethyl-4-(6-((5-(2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added2-phenylcyclopropane-1-carboxylic acid (36 mg, 0.22 mmol) and EDC.HCl(43 mg, 0.22 mmol), the reaction mixture was stirred at 50° C. for 2 hto give a brown solution. LCMS (Rt=0.848 min; MS Calc'd: 477.2; MSFound: 478.1 [M+H]⁺). The mixture was concentrated under reducedpressure to give a residue. The residue was purified by washing withMeOH/water (5 mL/1 mL) to give a crude product. Then further purified byprep-HPLC (0.05% NH₃.H₂O as an additive) to give an impure product (30mg, purity: 89.8%). Then further purified by prep-HPLC (0.225% FA as anadditive) to giveN,N-dimethyl-4-(6-((5-(2-phenylcyclopropane-1-carboxamido)pyridin-3-yl)amino)pyridin-3-yl)benzamide(23.9 mg, yield: 33%) as a white solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 100%, Rt=2.568 min; MS Calc'd: 477.2; MS Found: 478.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.38-1.47 (1H, m), 1.48-1.59 (1H,m), 2.11-2.22 (1H, m), 2.40-2.55 (1H, m), 2.90-3.06 (6H, m), 7.00 (1H,d, J=8.8 Hz), 7.16-7.23 (3H, m), 7.25-7.33 (2H, m), 7.49 (2H, d, J=8.4Hz), 7.73 (2H, d, J=8.4 Hz), 7.95-8.04 (1H, m), 8.39-8.45 (1H, m),8.52-8.60 (2H, m), 8.70-8.76 (1H, m), 9.61 (1H, br s), 10.55 (1H, br s).

Example 139:4-(6-((5-(4-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of 4-fluorobenzoic acid (32 mg, 0.22 mmol) in DMF (5 mL)was added HATU (142 mg, 0.37 mmol) and TEA (38 mg, 0.37 mmol), thereaction mixture was stirred at 25° C. for 0.5 hour, then added4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol), the resulting mixture was stirred at 25° C. for 16 h togive a saffron solution. LCMS (Rt=0.752 min; MS Calc'd: 455.2; MS Found:470.2 [M+H]⁺). The mixture was diluted with water (10 mL), thenextracted with DCM (10 mL×2). The combined extracts were washed withbrine (15 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by washingwith MeOH (5 mL). The filter cake was further purified by prep-HPLC(0.05% NH₃.H₂O as an additive) purification to give4-(6-((5-(4-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(8.7 mg, yield: 13%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.642 min; MS Calc'd: 455.2; MS Found:456.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.95-3.04 (6H, m), 7.00 (1H,d, J=8.8 Hz), 7.40 (2H, t, J=8.8 Hz), 7.48 (2H, d, J=8.4 Hz), 7.73 (2H,d, J=8.4 Hz), 7.98-8.03 (1H, m), 8.04-8.10 (2H, m), 8.49 (1H, d, J=2.4Hz), 8.58 (1H, d, J=2.0 Hz), 8.68 (1H, t, J=2.4 Hz), 8.71 (1H, t, J=2.8Hz), 9.52 (1H, br s), 10.45 (1H, br s).

Example 140:4-(6-((5-(3-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of 3-fluorobenzoic acid (32 mg, 0.22 mmol) in DMF (5 mL)was added TEA (38 mg, 0.37 mmol) and HATU (142 mg, 0.37 mmol), thereaction mixture was stirred at 25° C. for 0.5 hour, then added4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol). The resulting mixture was stirred at 25° C. for 16 h togive a saffron solution. LCMS (Rt=0.761 min; MS Calc'd: 455.2; MS Found:478.2 [M+Na]+). The mixture was diluted with water (10 mL), thenextracted with DCM (10 mL×2), the combined extracts were washed withbrine (15 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was purified by washingwith MeOH (5 mL). The filter cake was further purified by prep-HPLC(0.05% NH₃.H₂O as an additive) to give4-(6-((5-(3-fluorobenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(11.4 mg, yield: 17%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.639 min; MS Calc'd: 455.2; MS Found:456.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.04 (6H, m), 7.00 (1H,d, J=8.8 Hz), 7.46-7.52 (3H, m), 7.58-7.65 (1H, m), 7.73 (2H, d, J=8.4Hz), 7.78-7.83 (1H, m), 7.83-7.87 (1H, m), 8.01 (1H, dd, J=8.8, 2.4 Hz),8.50 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.4 Hz), 8.70 (1H, d, J=2.4 Hz),8.72 (1H, d, J=2.4 Hz), 9.53 (1H, br s), 10.51 (1H, br s).

Example 141:4-(6-((5-(3-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added 3-methoxybenzoic acid (34mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reaction mixture wasstirred at 50° C. for 2 h to give a brown solution. LCMS (Rt=0.770 min;MS Calc'd: 467.2; MS Found: 468.1 [M+H]⁺). The mixture was concentratedunder reduced pressure to give a residue. The residue was purified bywashing with MeOH/water (5 mL/1 mL) to give a crude product. Thenfurther purified by prep-HPLC (0.05% NH₃.H₂O as an additive) to give4-(6-((5-(3-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(23.6 mg, yield: 34%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.636 min; MS Calc'd: 467.2; MS Found:468.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.98 (6H, s), 3.85 (3H, s),7.00 (1H, d, J=8.8 Hz), 7.19 (1H, dd, J=8.4, 2.4 Hz), 7.45-7.53 (4H, m),7.58 (1H, d, J=8.0 Hz), 7.73 (2H, d, J=8.4 Hz), 8.00 (1H, dd, J=8.8, 2.4Hz), 8.49 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.4 Hz), 8.65-8.73 (2H, m),9.50 (1H, br s), 10.39 (1H, br s).

Example 142:4-(6-((5-(4-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added 3-methoxybenzoic acid (34mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reaction mixture wasstirred at 50° C. for 2 h to give a brown suspension. LCMS (Rt=0.778min; MS Calc'd: 467.2; MS Found: 468.1 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by washing with MeOH (5 mL) to give a crude product. Thenfurther purified by prep-HPLC (0.05% NH₃.H₂O as an additive) to give4-(6-((5-(4-methoxybenzamido)pyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide(20.3 mg, yield: 29%) as a pale yellow powder. LCMS (Shimadzu LCMS 2010,Mobile phase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and60% [MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 100%, Rt=1.645 min; MS Calc'd: 467.2; MS Found:468.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.96-3.05 (6H, m), 3.85 (3H,s), 7.00 (1H, d, J=8.8 Hz), 7.09 (2H, d, J=8.4 Hz), 7.48 (2H, d, J=8.0Hz), 7.73 (2H, d, J=8.0 Hz), 7.95-8.04 (3H, m), 8.49 (1H, d, J=2.0 Hz),8.58 (1H, d, J=2.8 Hz), 8.65-8.70 (2H, m), 9.48 (1H, br s), 10.27 (1H,br s).

Example 143:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-4-carboxamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (50mg, 0.15 mmol) in pyridine (2 mL) was added 1H-indole-4-carboxylic acid(36 mg, 0.22 mmol) and EDC.HCl (43 mg, 0.22 mmol), the reaction mixturewas stirred at 50° C. for 2 h to give a brown solution. LCMS (Rt=0.757min; MS Calc'd: 476.2; MS Found: 477.0 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give a residue. The residue waspurified by washing with MeOH/water (5 mL/1 mL) to give a crude product.Then further purified by prep-HPLC (0.05% NH₃.H₂O as an additive) togiveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-indole-4-carboxamide(27.2 mg, yield: 38%) as a white solid. LCMS (Shimadzu LCMS 2010, Mobilephase: from 100% [water+0.04% TFA] to 40% [water+0.04% TFA] and 60%[MeCN+0.02% TFA] in 1.35 min, then under this condition for 0.9 min,finally changed to 100% [water+0.04% TFA] and under this condition for0.75 min) purity is 99.23%, Rt=1.598 min; MS Calc'd: 476.2; MS Found:477.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.09 (6H, m), 6.85-6.89(1H, m), 7.01 (1H, d, J=8.4 Hz), 7.23 (1H, t, J=7.6 Hz), 7.45-7.56 (3H,m), 7.57-7.65 (2H, m), 7.73 (2H, d, J=8.0 Hz), 8.00 (1H, dd, J=8.8, 2.8Hz), 8.50 (1H, d, J=2.0 Hz), 8.59 (1H, d, J=2.8 Hz), 8.70 (1H, d, J=2.4Hz), 8.77 (1H, d, J=2.0 Hz), 9.48 (1H, br s), 10.35 (1H, br s), 11.39(1H, br s).

Example 144:N-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide

To a mixture of4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)-N,N-dimethylbenzamide (80mg, 0.24 mmol) in pyridine (2 mL) was added1H-benzo[d]imidazole-4-carboxylic acid (58 mg, 0.36 mmol) and EDC.HCl(92 mg, 0.48 mmol), the reaction mixture was stirred at 50° C. for 2 hto give a brown suspension. LCMS (Rt=0.660 min; MS Calc'd: 477.2; MSFound: 478.1 [M+H]⁺). The mixture was concentrated under reducedpressure to give a residue. The residue was purified by washing withMeOH (5 mL) to give a crude product. Then further purified by prep-HPLC(0.225% FA as an additive) to giveN-(5-((5-(4-(dimethylcarbamoyl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-1H-benzo[d]imidazole-4-carboxamide(7.9 mg, yield: 7%) as a white solid. LCMS (Agilent LCMS 1200-6140A,mobile phase: from 99% [water+0.1% FA] and 1% [MeCN+0.1% FA] to 95%[water+0.1% FA] and 5% [MeCN+0.1% FA] in 0.6 min, then changed to 100%[MeCN+0.1% FA] under this condition for 3.4 min, finally back to 99%[water+0.1% FA] and 1% [MeCN+0.1% FA] and under this condition for 0.5min.) purity is 97.48%, Rt=2.126 min; MS Calc'd: 477.2; MS Found: 478.3[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.91-3.05 (6H, m), 7.04 (1H, d,J=8.8 Hz), 7.45-7.53 (3H, m), 7.76 (2H, d, J=8.4 Hz), 7.85-7.94 (1H, m),8.00-8.07 (2H, m), 8.61-8.72 (3H, m), 8.74-8.80 (1H, m), 8.83-8.92 (1H,m), 9.75 (1H, br s).

Example 145:3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

Step 1: Preparation of 3-bromoquinoline-5-carboxamide

To a solution of 3-bromoquinoline-5-carboxylic acid (50 mg, 0.20 mmol)and NH₄Cl (21 mg, 0.40 mmol) in pyridine (1 mL) was added EDCI (114 mg,0.595 mmol) under N₂ atmosphere. The mixture was stirred at 18-20° C.for 16 h under N₂ atmosphere. A white suspension was formed. LCMS(Rt=0.630 min; MS Calc'd: 250.0; MS Found: 250.8 [M+H]⁺). The mixturewas concentrated under reduced pressure. The residue was poured intowater (10 mL) and extracted with DCM (10 mL×3). The combined organiclayer was dried over Na₂SO₄, filtered and concentrated in vacuum to give3-bromoquinoline-5-carboxamide (60 mg, crude) as a white solid. LCMS is40% (Rt=0.629 min; MS Calc'd: 250.0; MS Found: 250.8 [M+H]⁺).

Step 2: Preparation of3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

A mixture of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg,0.20 mmol), 3-bromoquinoline-5-carboxamide (50 mg, crude), Pd₂(dba)₃ (9mg, 0.010 mmol), Brettphos (11 mg, 0.020 mmol) and Cs₂CO₃ (193 mg, 0.592mmol) in dioxane (3 mL) was stirred at 100° C. for 16 h.

Example 146:N-methyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

Step 1: Preparation of 3-bromo-N-methylquinoline-5-carboxamide

To a solution of 3-bromoquinoline-5-carboxylic acid (50 mg, 0.20 mmol)and MeNH₂—HCl (12 mg, 0.40 mmol) in pyridine (1 mL) was added EDCI (114mg, 0.595 mmol) under N₂ atmosphere. The mixture was stirred at 18-20°C. for 16 h under N₂ atmosphere. A white suspension was formed. LCMS(Rt=0.683 min; MS Calc'd: 264.0; MS Found: 264.6 [M+H]⁺). The mixturewas concentrated under reduced pressure. The residue was poured intowater (10 mL) and extracted with DCM (10 mL×3). The combined organiclayer was washed with water (10 mL), dried over Na₂SO₄, filtered andconcentrated in vacuum to give 3-bromo-N-methylquinoline-5-carboxamide(55 mg, crude) as a white solid. LCMS is 21% (Rt=0.788 min; MS Calc'd:264.0; MS Found: 265.7 [M+H]⁺).

Step 2: Preparation ofN-methyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

A mixture of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg,0.20 mmol), 3-bromo-N-methylquinoline-5-carboxamide (52 mg, crude),Pd₂(dba)₃ (9 mg, 0.01 mmol), Brettphos (11 mg, 0.02 mmol) and Cs₂CO₃(193 mg, 0.592 mmol) in dioxane (3 mL) was stirred at 100° C. for 16 h.A black suspension was formed. LCMS (Rt=0.685 min; MS Calc'd: 437.2; MSFound: 438.0 [M+H]⁺). The mixture was filtered and concentrated to givean orange gum. The residue was purified by prep-HPLC (0.05% HCl as anadditive) and lyophilized to giveN-methyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide(4.6 mg, yield for 2 steps: 5%) as a yellow solid. LCMS (Shimadzu LCMS2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA]to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, thenunder this condition for 0.9 min, finally changed to 90% [water+0.04%TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.)purity is 98.83%, Rt=1.244 min; MS Calc'd.: 437.2; MS Found: 438.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 2.09 (2H, t, J=7.2 Hz), 2.50-2.56(2H, m, overlapped with DMSO signal), 2.89 (3H, d, J=4.4 Hz), 3.88 (2H,t, J=6.8 Hz), 7.09 (1H, d, J=8.4 Hz), 7.65-7.85 (6H, m), 8.06 (1H, d,J=2.0 Hz), 8.15 (1H, d, J=8.4 Hz), 8.59 (1H, s), 8.67 (1H, d, J=4.8 Hz),9.20 (1H, s), 9.60 (1H, s), 10.22 (1H, br s).

Example 147:N,N-dimethyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

Step 1: Preparation of 3-bromo-N,N-dimethylquinoline-5-carboxamide

To a mixture of 3-bromoquinoline-5-carboxylic acid (50 mg, 0.20 mmol) inpyridine (2 mL) was added EDCI (76 mg, 0.40 mmol) andN-methylmethanamine (65 mg, 0.79 mmol, HCl salt). The reaction mixturewas stirred at 50° C. for 2 h to give a brown suspension. LCMS (Rt=0.661min; MS Calc'd: 278.0; MS Found: 278.8 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give a residue. 20 mL water wasadded. The mixture was extracted with EtOAc (15 mL×2). The combinedextract was washed with brine (20 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give3-bromo-N,N-dimethylquinoline-5-carboxamide (48 mg, yield: 86%) as ayellow solid. ¹H NMR (400 MHz, CDCl₃) δ 2.79 (3H, s), 3.13 (3H, s), 7.64(1H, dd, J=7.6, 1.6 Hz), 7.82-7.88 (1H, m), 8.11 (1H, dt, J=8.4, 0.8Hz), 8.36 (1H, dd, J=2.4, 0.8 Hz), 9.03 (1H, d, J=2.4 Hz).

Step 2: Preparation ofN,N-dimethyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide

A mixture of Pd₂(dba)₃ (16 mg, 0.020 mmol) and Brettphos (9 mg, 0.02mmol) in dioxane (3 mL) was stirred at 50° C. under N₂ atmosphere for 10min. Then added into a mixture of1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg, 0.20 mmol),3-bromo-N,N-dimethylquinoline-5-carboxamide (48 mg, 0.17 mmol) andCs₂CO₃ (112 mg, 0.344 mmol) in dioxane (5 mL). The reaction mixture wasstirred at 100° C. under N₂ atmosphere for 16 h to give a brownsuspension. LCMS (Rt=0.689 min; MS Calc'd: 451.2; MS Found: 452.1[M+H]⁺). The mixture was filtered. The filter cake was washed with DCM(5 mL×2). The filtrate was concentrated under reduced pressure to give aresidue. The residue was purified by prep-HPLC (0.05% NH₃H₂O as anadditive) purification to give 40 mg of product. But it contained n-BuOH(confirmed by HNMR). The impure product was further purified byprep-HPLC (normal phase, [Hexane-IPA]) and lyophilized to giveN,N-dimethyl-3-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)quinoline-5-carboxamide(20.7 mg, yield: 27%) as a yellow solid. LCMS (Shimadzu LCMS 2010,Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA] to 20%[water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, then under thiscondition for 0.9 min, finally changed to 90% [water+0.04% TFA] and 10%[MeCN+0.02% TFA] and under this condition for 0.75 min.) purity is99.88%, Rt=1.591 min; MS Calc'd.: 451.2; MS Found: 452.1 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 2.01-2.16 (2H, m), 2.50-2.56 (2H, m, overlappedwith DMSO signal), 2.80 (3H, s), 3.19 (3H, s), 3.87 (2H, t, J=7.2 Hz),7.03 (1H, d, J=8.8 Hz), 7.46 (1H, d, J=7.2 Hz), 7.56 (1H, t, J=7.2 Hz),7.65-7.80 (4H, m), 7.95 (1H, d, J=8.4 Hz), 8.00 (1H, dd, J=8.8, 2.8 Hz),8.57 (1H, d, J=2.4 Hz), 8.75 (1H, d, J=2.0 Hz), 9.12 (1H, d, J=2.4 Hz),9.83 (1H, br s).

Example 148:1-(4-(6-((5-(pyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Preparation of (3-bromoquinolin-5-yl)(pyrrolidin-1-yl)methanone

A mixture of 3-bromoquinoline-5-carboxylic acid (50 mg, 0.20 mmol) inSOCl₂ (1.64 g, 13.8 mmol) was stirred at 80° C. for 1 hour. The mixturewas concentrated and dissolved in DCM (3 mL). To above solution wasadded pyrrolidine (28 mg, 0.40 mmol) and TEA (60 mg, 0.60 mmol). Themixture was stirred at 25° C. for 1 hour. A white suspension was formed.LCMS (Rt=0.759 min; MS Calc'd: 304.0; MS Found: 304.7 [M+H]⁺). Themixture was concentrated under reduced pressure. The residue was pouredinto water (10 mL) and extracted with DCM (10 mL×3). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuumto give (3-bromoquinolin-5-yl)(pyrrolidin-1-yl)methanone (50 mg, crude)as a white solid.

Step 2: Preparation of1-(4-(6-((5-(pyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg,0.20 mmol), (3-bromoquinolin-5-yl)(pyrrolidin-1-yl)methanone (60 mg,0.20 mmol), Pd₂(dba)₃ (9 mg, 0.01 mmol), Brettphos (11 mg, 0.020 mmol)and Cs₂CO₃ (193 mg, 0.592 mmol) in dioxane (3 mL) was stirred at 100° C.for 16 h. A black suspension was formed. LCMS (Rt=0.741 min; MS Calc'd:477.2; MS Found: 478.0 [M+H]⁺). The mixture was filtered andconcentrated to give an orange gum. The residue was purified byprep-HPLC (0.05% HCl as an additive) and lyophilized to give1-(4-(6-((5-(pyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(5.8 mg, yield for 2 steps: 6%) as a yellow solid. LCMS (Shimadzu LCMS2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA]to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, thenunder this condition for 0.9 min, finally changed to 90% [water+0.04%TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.)purity is 98.49%, Rt=1.347 min; MS Calc'd.: 477.2; MS Found: 478.1[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.74-1.89 (2H, m), 1.89-2.04 (2H,m), 2.04-2.17 (2H, m), 2.50-2.56 (2H, m, overlapped with DMSO signal),3.14 (2H, t, J=6.8 Hz), 3.68 (2H, t, J=6.8 Hz), 3.88 (2H, t, J=7.2 Hz),7.07 (1H, d, J=8.4 Hz), 7.55-7.61 (1H, m), 7.61-7.69 (1H, m), 7.69-7.80(4H, m), 7.95-8.09 (2H, m), 8.54 (1H, d, J=2.4 Hz), 8.90 (1H, d, J=2.4Hz), 9.28 (1H, d, J=2.0 Hz), 10.07 (1H, br s).

Example 149:1-(4-(6-((5-(3-hydroxypyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Preparation of(3-bromoquinolin-5-yl)(3-hydroxypyrrolidin-1-yl)methanone

A mixture of 3-bromoquinoline-5-carboxylic acid (50 mg, 0.20 mmol) inSOCl₂ (1.64 g, 13.8 mmol) was stirred at 80° C. for 1 hour. The mixturewas concentrated and dissolved in DCM (3 mL). To the solution was addedpyrrolidin-3-ol (35 mg, 0.40 mmol) and TEA (60 mg, 0.60 mmol). Themixture was stirred at 25° C. for 1 hour. A white suspension was formed.LCMS (Rt=0.792 min; MS Calc'd: 320.0; MS Found: 322.9 [M+H]⁺). Themixture was concentrated under reduced pressure. The residue was pouredinto water (10 mL) and extracted with DCM (10 mL×3). The combinedorganic layer was dried over Na₂SO₄, filtered and concentrated in vacuumto give (3-bromoquinolin-5-yl)(3-hydroxypyrrolidin-1-yl)methanone (50mg, crude) as a white solid. LCMS is 99% (Rt=0.658 min; MS Calc'd:320.0; MS Found: 320.7 [M+H]⁺).

Step 2: Preparation of1-(4-(6-((5-(3-hydroxypyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg,0.20 mmol), (3-bromoquinolin-5-yl)(3-hydroxypyrrolidin-1-yl)methanone(63 mg, 0.20 mmol), Pd₂(dba)₃ (9 mg, 0.01 mmol), Brettphos (11 mg, 0.02mmol) and Cs₂CO₃ (193 mg, 0.592 mmol) in dioxane (3 mL) was stirred at100° C. for 16 h. A black suspension was formed. LCMS (Rt=1.203 min; MSCalc'd: 493.2; MS Found: 494.2 [M+H]⁺). The mixture was filtered andconcentrated to give an orange gum. The residue was purified byprep-HPLC (0.05% HCl as an additive) and lyophilized to give1-(4-(6-((5-(3-hydroxypyrrolidine-1-carbonyl)quinolin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(21.3 mg, yield for 2 steps: 22%) as a yellow solid. LCMS (Shimadzu LCMS2010, Mobile phase: from 90% [water+0.04% TFA] and 10% [MeCN+0.02% TFA]to 20% [water+0.04% TFA] and 80% [MeCN+0.02% TFA] in 1.35 min, thenunder this condition for 0.9 min, finally changed to 90% [water+0.04%TFA] and 10% [MeCN+0.02% TFA] and under this condition for 0.75 min.)purity is 98.43%, Rt=1.210 min; MS Calc'd.: 493.2; MS Found: 494.2[M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 1.70-2.15 (4H, m), 2.50-2.56 (2H, m,overlapped with DMSO signal), 2.91-3.25 (1H, m), 3.30-3.45 (1H, m),3.52-3.80 (2H, m), 3.82-3.92 (2H, m), 3.30-4.50 (1H, m, overlapped withH₂O signal), 7.06-7.16 (1H, m), 7.65-7.84 (6H, m), 8.04-8.11 (1H, m),8.15-8.25 (1H, m), 8.58 (0.5H, d, J=2.4 Hz), 8.63 (0.5H, d, J=2.0 Hz),8.98 (0.5H, d, J=2.0 Hz), 9.07 (0.5H, s), 9.55 (0.5H, d, J=2.0 Hz), 9.64(0.5H, d, J=2.0 Hz), 10.57 (1H, br s).

Example 150:1-(4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.079mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)(cyclopropyl)methanone(112 mg, 0.395 mmol) in dioxane (5 mL) and Cs₂CO₃ (386 mg, 1.18 mmol)were added and the resulting mixture was stirred at 100° C. for 18 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.555 min; MS Calc'd: 455.2; MS Found: 456.1 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give1-(4-(6-((1-(cyclopropanecarbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(24.0 mg, yield: 13%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ0.92-1.00 (4H, m), 2.03-2.12 (2H, m), 2.17-2.26 (1H, m), 2.55 (2H,overlaped with DMSO), 3.86 (2H, t, J=6.8 Hz), 3.94-4.03 (2H, m), 4.36(2H, t, J=4.0 Hz), 6.86 (1H, d, J=8.4 Hz), 7.64 (2H, d, J=8.0 Hz), 7.72(2H, d, J=8.4 Hz), 7.89 (1H, d, J=8.4 Hz), 8.21 (1H, br s), 8.43 (1H,s), 8.65 (1H, s), 9.21 (1H, s).

Example 151: methyl7-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.079mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),methyl 7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(108 mg, 0.395 mmol) in dioxane (5 mL) and Cs₂CO₃ (386 mg, 1.18 mmol)were added and the resulting mixture was stirred at 100° C. for 18 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.549 min; MS Calc'd: 445.2; MS Found: 446.0 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (normal,hexane-EtOH) and triturated with EtOAc (1 mL) to give methyl7-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-1-carboxylate(15.7 mg, yield: 9%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.03-2.12 (2H, m), 2.55 (2H, overlaped with DMSO), 3.78 (3H, s),3.83-3.89 (4H, m), 4.30 (2H, t, J=4.4 Hz), 6.87 (1H, d, J=9.2 Hz), 7.65(2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.89 (1H, dd, J=8.4, 2.4 Hz),8.29 (1H, d, J=2.0 Hz), 8.46 (1H, d, J=2.4 Hz), 8.66 (1H, br s), 9.15(1H, s).

Example 152:1-(4-(6-((1-isobutyryl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.079mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2-methylpropan-1-one(112 mg, 0.395 mmol) in dioxane (4 mL) and Cs₂CO₃ (386 mg, 1.18 mmol)were added and the resulting mixture was stirred at 100° C. for 18 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.569 min; MS Calc'd: 457.2; MS Found: 458.1 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.225% FA as anadditive) to give1-(4-(6-((1-isobutyryl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(25.6 mg, yield: 14%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.12 (6H, d, J=6.4 Hz), 2.02-2.12 (2H, m), 2.52 (2H, overlaped withDMSO), 3.16-3.26 (1H, m), 3.86 (2H, t, J=6.8 Hz), 3.92 (2H, t, J=4.4Hz), 4.35 (2H, t, J=4.0 Hz), 6.86 (1H, d, J=8.8 Hz), 7.65 (2H, d, J=8.8Hz), 7.72 (2H, d, J=8.8 Hz), 7.89 (1H, dd, J=8.4, 2.4 Hz), 8.30 (1H, brs), 8.44 (1H, d, J=2.4 Hz), 8.58 (1H, s), 9.18 (1H, s).

Example 153:1-(4-(6-((1-(isopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (30 mg, 0.034 mmol) and Brettphos (36 mg, 0.067mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (85 mg, 0.34 mmol),7-bromo-1-(isopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(108 mg, 0.336 mmol) in dioxane (4 mL) and Cs₂CO₃ (328 mg, 1.01 mmol)were added and the resulting mixture was stirred at 100° C. for 16 h. Ablack brown mixture was formed. LCMS showed the purity of the desired(Rt=0.588 min; MS Calc'd: 493.1; MS Found: 494.0 [M+H]⁺). The reactionmixture was diluted with DCM (10 mL), filtered and concentrated. Theresidue was purified by prep-HPLC (0.05% NH₃.H₂O as an additive) to give1-(4-(6-((1-(isopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(33.3 mg, yield: 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.33(6H, d, J=6.8 Hz), 2.03-2.11 (2H, m), 2.52 (2H, overlaped with DMSO),3.70-3.78 (1H, m), 3.81 (2H, t, J=4.0 Hz), 3.85 (2H, t, J=6.8 Hz), 4.34(2H, t, J=4.0 Hz), 6.86 (1H, d, J=8.4 Hz), 7.65 (2H, d, J=8.8 Hz), 7.72(2H, d, J=8.8 Hz), 7.90 (1H, dd, J=8.8, 2.4 Hz), 8.30 (1H, d, J=2.0 Hz),8.35 (1H, d, J=2.0 Hz), 8.43 (1H, d, J=2.4 Hz), 9.23 (1H, s).

Example 154:1-(4-(6-((1-(cyclopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (54 mg, 0.059 mmol) and Brettphos (64 mg, 0.118mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (150 mg, 0.592 mmol),7-bromo-1-(cyclopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine(284 mg, 0.888 mmol) in dioxane (9 mL) and Cs₂CO₃ (579 mg, 1.01 mmol)were added and the resulting mixture was stirred at 100° C. for 18 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.575 min; MS Calc'd: 491.2; MS Found: 492.1 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.225% FA as anadditive) to give1-(4-(6-((1-(cyclopropylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(5.0 mg, yield: 2%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.02-1.11 (4H, m), 2.03-2.13 (2H, m), 2.56 (2H, overlaped with DMSO),2.85-2.94 (1H, m), 3.81-3.92 (4H, m), 4.39 (2H, t, J=4.0 Hz), 6.86 (1H,d, J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=9.2 Hz), 7.90 (1H,dd, J=9.2, 2.4 Hz), 8.38 (1H, s), 8.41 (1H, d, J=2.4 Hz), 8.45 (1H, d,J=1.6 Hz), 9.25 (1H, s).

Example 155:1-(4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (18 mg, 0.020 mmol) and Brettphos (21 mg, 0.039mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),1-(7-bromo-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-1-yl)-2,2-dimethylpropan-1-one(118 mg, 0.395 mmol) in dioxane (4 mL) and Cs₂CO₃ (257 mg, 0.790 mmol)were added and the resulting mixture was stirred at 100° C. for 12 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.599 min; MS Calc'd: 471.2; MS Found: 472.0 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by Combi Flash (DCM) andtriturated with EtOAc (2 mL) to give1-(4-(6-((1-pivaloyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(14.8 mg, yield: 8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.32(9H, s), 2.03-2.13 (2H, m), 2.56 (2H, overlaped with DMSO), 3.86 (2H, t,J=6.8 Hz), 4.02 (2H, t, J=4.8 Hz), 4.36 (2H, t, J=4.8 Hz), 6.84 (1H, d,J=8.8 Hz), 7.65 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.88 (1H, dd,J=8.4, 2.4 Hz), 8.28 (1H, d, J=2.4 Hz), 8.43 (1H, d, J=2.8 Hz), 8.45(1H, d, J=2.4 Hz), 9.10 (1H, s).

Example 156:1-(4-(6-((1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-7-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.080mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),7-bromo-1-(methylsulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (115mg, 0.395 mmol) in dioxane (4 mL) and Cs₂CO₃ (386 mg, 1.18 mmol) wereadded and the resulting mixture was stirred at 100° C. for 12 h. A blackbrown mixture was formed. LCMS showed the purity of the desired product(Rt=0.553 min; MS Calc'd: 465.1; MS Found: 465.9 [M+H]⁺). The reactionmixture was diluted with DCM (10 mL), filtered and concentrated. Theresidue was purified by prep-HPLC (0.05% NH₃.H₂O as an additive) to give(13.7 mg, yield: 7%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.03-2.15 (2H, m), 2.56 (2H, overlaped with DMSO), 3.22 (3H, s), 3.83(2H, t, J=4.4 Hz), 3.87 (2H, t, J=6.4 Hz), 4.37 (2H, t, J=4.0 Hz), 6.87(1H, d, J=9.2 Hz), 7.66 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.8 Hz), 7.91(1H, dd, J=8.8, 2.8 Hz), 8.37 (1H, d, J=2.4 Hz), 8.40 (1H, d, J=2.4 Hz),8.47 (1H, d, J=2.0 Hz), 9.24 (1H, s).

Example 157:N-methyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide

A mixture of Pd₂(dba)₃ (18 mg, 0.020 mmol) and Brettphos (21 mg, 0.039mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),N-(5-bromopyridin-3-yl)-N-methylmethanesulfonamide (105 mg, 0.395 mmol)in dioxane (5 mL) and Cs₂CO₃ (257 mg, 0.790 mmol) were added and theresulting mixture was stirred at 100° C. for 12 h. A black brown mixturewas formed. LCMS showed the purity of the desired product (Rt=0.574 min;MS Calc'd: 437.1; MS Found: 437.9 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL), filtered and concentrated. The residue waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) to giveN-methyl-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide(15.0 mg, yield: 9%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ2.15-2.25 (2H, m), 2.65 (2H, t, J=8.0 Hz), 2.94 (3H, s), 3.41 (3H, s),3.92 (2H, t, J=6.8 Hz), 6.63 (1H, s), 6.88 (1H, d, J=8.4 Hz), 7.55 (2H,d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 7.79 (1H, dd, J=8.8, 2.8 Hz),8.24-8.27 (2H, m), 8.49 (1H, d, J=2.0 Hz), 8.56 (1H, d, J=2.4 Hz).

Example 158:N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)acetamide

A mixture of Pd₂(dba)₃ (29 mg, 0.032 mmol) and Brettphos (34 mg, 0.063mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (80 mg, 0.316 mmol),N-(5-bromo-2-methoxypyridin-3-yl)acetamide (77 mg, 0.316 mmol) indioxane (4 mL) and Cs₂CO₃ (309 mg, 0.947 mmol) were added and theresulting mixture was stirred at 100° C. for 12 h. A black brown mixturewas formed. LCMS showed the purity of the desired product (Rt=0.543 min;MS Calc'd: 417.1; MS Found: 418.0 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL), filtered and concentrated. The residue waspurified by prep-HPLC (0.225% FA as an additive) to giveN-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)acetamide(26.2 mg, yield: 20%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.03-2.10 (2H, m), 2.12 (3H, s), 2.56 (2H, overlaped with DMSO), 3.86(2H, t, J=6.8 Hz), 3.90 (3H, s), 6.85 (1H, d, J=8.8 Hz), 7.64 (2H, d,J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.87 (1H, dd, J=8.8, 2.4 Hz), 8.38(1H, d, J=2.4 Hz), 8.44 (1H, d, J=2.4 Hz), 8.57 (1H, d, J=2.4 Hz), 9.08(1H, s), 9.33 (1H, s).

Example 159:N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.079mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),N-(5-bromo-2-methoxypyridin-3-yl)methanesulfonamide (111 mg, 0.395 mmol)in dioxane (4 mL) and Cs₂CO₃ (386 mg, 1.18 mmol) were added and theresulting mixture was stirred at 100° C. for 12 h. A black brown mixturewas formed. LCMS showed the purity of the desired product (Rt=0.537 min;MS Calc'd: 453.1; MS Found: 454.1 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL), filtered and concentrated. The residue waspurified by prep-HPLC (0.225% FA as an additive) and triturated (1 mL)to giveN-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)methanesulfonamide(19.1 mg, yield: 11%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.03-2.10 (2H, m), 2.56 (2H, overlaped with DMSO), 3.04 (3H, s), 3.86(2H, t, J=6.8 Hz), 3.88 (3H, s), 6.86 (1H, d, J=8.8 Hz), 7.65 (2H, d,J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.89 (1H, dd, J=8.8, 2.4 Hz), 8.01(1H, d, J=2.4 Hz), 8.40 (1H, d, J=2.4 Hz), 8.46 (1H, d, J=2.0 Hz), 9.17(1H, s), 9.19 (1H, s).

Example 160:N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylacetamide

A mixture of Pd₂(dba)₃ (36 mg, 0.039 mmol) and Brettphos (42 mg, 0.079mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (100 mg, 0.395 mmol),N-(5-bromo-2-methoxypyridin-3-yl)-N-methylacetamide (102 mg, 0.395 mmol)in dioxane (4 mL) and Cs₂CO₃ (386 mg, 1.18 mmol) were added and theresulting mixture was stirred at 100° C. for 12 h. A black brown mixturewas formed. LCMS showed the purity of the desired product (Rt=0.553 min;MS Calc'd: 431.2; MS Found: 432.0 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL), filtered and concentrated. The residue waspurified by prep-HPLC (0.225% FA as an additive) to giveN-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylacetamide(17.4 mg, yield: 10%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ 1.75(3H, s), 2.04-2.12 (2H, m), 2.44 (2H, overlaped with DMSO), 3.06 (3H,s), 3.86 (2H, t, J=6.8 Hz), 3.89 (3H, s), 6.88 (1H, d, J=8.4 Hz), 7.66(2H, d, J=8.4 Hz), 7.73 (2H, d, J=8.8 Hz), 7.92 (1H, dd, J=8.0, 1.2 Hz),8.21 (1H, s), 8.42 (1H, s), 8.49 (1H, s), 9.27 (1H, s).

Example 161:N-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylmethanesulfonamide

A mixture of Pd₂(dba)₃ (29 mg, 0.032 mmol) and Brettphos (34 mg, 0.063mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(6-Aminopyridin-3-yl)phenyl)pyrrolidin-2-one (80 mg, 0.316 mmol),N-(5-bromo-2-methoxypyridin-3-yl)-N-methylmethanesulfonamide (93 mg,0.316 mmol) in dioxane (5 mL) and Cs₂CO₃ (309 mg, 0.947 mmol) were addedand the resulting mixture was stirred at 100° C. for 12 h. A black brownmixture was formed. LCMS showed the purity of the desired product(Rt=0.573 min; MS Calc'd: 467.1; MS Found: 468.0 [M+H]⁺). The reactionmixture was diluted with DCM (10 mL), filtered and concentrated. Theresidue was purified by prep-HPLC (0.225% FA as an additive) to giveN-(2-methoxy-5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-N-methylmethanesulfonamide(20.3 mg, yield: 14%) as a yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.03-2.10 (2H, m), 2.56 (2H, overlaped with DMSO), 3.05 (3H, s), 3.17(3H, s), 3.86 (2H, t, J=7.2 Hz), 3.91 (3H, s), 6.86 (1H, d, J=8.4 Hz),7.66 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=9.2 Hz), 7.91 (1H, dd, J=8.8, 2.4Hz), 8.16 (1H, d, J=2.8 Hz), 8.47 (1H, d, J=2.4 Hz), 8.50 (1H, d, J=2.4Hz), 9.24 (1H, s).

Example 162:(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 1-(4-(5-bromopyrazin-2-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(300 mg, 1.04 mmol), 2,5-dibromopyrazine (621 mg, 2.61 mmol),Pd(dppf)Cl₂ (76.4 mg, 0.104 mmol) and K₂CO₃ (433 mg, 3.13 mmol) weretaken up in dioxane (20 mL) and H₂O (4 mL) and the resulting mixture wasstirred at 80° C. for 16 h. A black solution was formed. LCMS (Rt=0.651min; MS Calc'd: 317.0; MS Found: 317.7 [M+H]⁺). The mixture wasconcentrated in vacuum. The residue was purified by Combi Flash (50%EtOAc in pentane) to give1-(4-(5-bromopyrazin-2-yl)phenyl)pyrrolidin-2-one (270 mg, yield: 81%)as a yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 2.17-2.60 (2H, m), 2.66(2H, t, J=8.0 Hz), 3.93 (2H, t, J=6.8 Hz), 7.80 (2H, d, J=8.8 Hz), 8.01(2H, d, J=9.2 Hz), 8.69 (1H, d, J=1.6 Hz), 8.76 (1H, d, J=1.6 Hz).

Step 2: Preparation of 1-(5-Amino-3-pyridyl)pyrrolidin-2-one

5-Bromopyridin-3-amine (10 g, 57.8 mmol), pyrrolidin-2-one (9 ml, 63.2mmol), K₂CO₃ (15 g, 115.6 mmol), CuI (1.1 g, 5.78 mmol) and DMEDA (1.3ml, 8.42 mmol) were taken up in 1,4-dioxane (100 ml) and the resultingmixture was refluxed overnight. After cooling to rt, EtOAc was added andthe mixture filtered through celite. The filtrate was concentrated andpurified on a silica gel column to give the product as a solid (6 g,59%). MS ES+m/z 178 [M+H]⁺.

Step 3: Preparation of(5S)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one

3-Bromo-2-chloro-5-nitro-pyridine (1 g, 4.21 mmol),(5S)-5-(hydroxymethyl)pyrrolidin-2-one (500 mg, 4.34 mmol) and K₂CO₃(700 mg, 5.06 mmol) were taken up in MeCN (10 ml) and the resultingmixture was stirred at 70° C. overnight. More(5S)-5-(hydroxymethyl)pyrrolidin-2-one (130 mg, 1.13 mmol) and K₂CO₃(300 mg, 2.17 mmol) were added and stirring continued at 70° C. for 5 h.After cooling to rt, the mixture was diluted with water (10 ml) andEtOAc (10 ml) and the organic layer separated. The remaining aqueouslayer was further extracted with EtOAc (2×10 ml) and the combinedorganics were washed with brine, dried over Na₂SO₄, filtered andconcentrated to give the product as a solid (1.13 g, 85%). MS ES+m/z 316[M+H]⁺.

Step 4: Preparation of(6S)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.02,6]trideca-1(9),10,12-trien-3-one

(5S)-5-[(3-bromo-5-nitro-2-pyridyl)oxymethyl]pyrrolidin-2-one (1.13 g,3.57 mmol), CuI (75 mg, 0.39 mmol), N,N′-dimethylethylenediamine (85 μl,0.8 mmol) and K₂CO₃ (0.99 g, 7.15 mmol) were taken up in EtOAc (20 ml)and the resulting mixture was stirred at 70° C. for 2 h. More CuI (75mg, 0.39 mmol) and N,N′-dimethylethylenediamine (85 μl, 0.8 mmol) wereadded and the mixture was refluxed for 2 h. Cs₂CO₃ (2 g, 6.14 mmol) and1,4-dioxane (20 ml) were added and stirring continued at 100° C.overnight. When cooled to rt the mixture was filtered through celite andrinsed with EtOAc (2×5 ml). The filtrate was washed with half-saturatedbrine (20 ml), dried over Na₂SO₄, filtered and concentrated to give theproduct as a solid (720 mg, 86%). MS ES+m/z 236 [M+H]⁺.

Step 5: Preparation of(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

(6S)-12-nitro-8-oxa-2,10-diazatricyclo[7.4.0.02,6]trideca-1(9),10,12-trien-3-one(357 mg, 1.52 mmol), Fe (509 mg, 9.11 mmol) and ammonium chloride (244mg, 4.55 mmol) were taken up in EtOH/H₂O (4:1, 12.5 ml) and theresulting mixture was refluxed for 1.5 h. After cooling to rt themixture was filtered through celite, rinsed with MeOH and the filtratewas concentrated. The resulting residue was suspended in water and pHwas adjusted to about ˜7 by careful addition of a sat. aq. NaHCO₃. Themixture was extracted with EtOAc and the combined organics were driedover Na₂SO₄, filtered and concentrated to give the product as a solid(212 mg, 68%). MS ES+m/z 206 [M+H]⁺.

Step 6: Preparation of(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of Pd₂(dba)₃ (37 mg, 0.041 mmol) and Brettphos (44 mg, 0.082mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.1-(4-(5-Bromopyrazin-2-yl)phenyl)pyrrolidin-2-one (130 mg, 0.409 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(84 mg, 0.409 mmol) in dioxane (5 mL) and Cs₂CO₃ (400 mg, 1.23 mmol)were added and the resulting mixture was stirred at 100° C. for 12 h. Ablack brown mixture was formed. LCMS showed the purity of the desiredproduct (Rt=0.696 min; MS Calc'd: 442.2; MS Found: 443.1 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(13.8 mg, yield: 8%) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ1.62-1.76 (1H, m), 2.04-2.13 (2H, m), 2.17-2.27 (1H, m), 2.32-2.42 (1H,m), 2.54 (2H, overlap with DMSO), 2.63-2.73 (1H, m), 3.84-3.95 (3H, m),4.04-4.11 (1H, m), 4.60 (1H, dd, J=10.8, 2.8 Hz), 7.76 (2H, d, J=8.8Hz), 8.01 (2H, d, J=8.4 Hz), 8.27 (1H, s), 8.44 (1H, d, J=2.8 Hz), 8.70(1H, s), 9.00 (1H, d, J=2.4 Hz), 9.70 (1H, s).

Example 163:1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one

Step 1: Preparation of1-(5-bromopyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one

To a solution of 1-(5-bromopyridin-3-yl)imidazolidin-2-one (100 mg,0.413 mmol) in DMF (2 mL) was added NaH (66 mg, 1.7 mmol, 60% purity)and then the mixture was stirred at 25° C. for 30 min. To the mixturewas added 4-(chloromethyl)thiazole (105 mg, 0.620 mmol, HCl salt) at 0°C. and the mixture was stirred at 25° C. for 3 h. A gray suspension wasformed. LCMS showed 1-(5-bromopyridin-3-yl)imidazolidin-2-one wasconsumed completely and desired product (Rt=0.560 min; MS Calc'd: 338.0;MS Found: 338.7[M+H]⁺) was detected. Amounts of crude1-(5-bromopyridin-3-yl)imidazolidin-2-one were increased using the samesynthetic procedure as above and poured into sat. aq. NH₄Cl (50 mL),extracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine (50 mL×6), dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by Combi Flash (EtOAc) to give1-(5-bromopyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one (288mg, 92% yield) as a yellow gum. ¹H NMR (400 MHz, CDCl₃) δ 3.60-3.70 (2H,m), 3.80-3.90 (2H, m), 4.66 (2H, s), 7.31 (1H, d, J=2.0 Hz), 8.34 (1H,d, J=2.0 Hz), 8.47 (1H, t, J=2.4 Hz), 8.52 (1H, d, J=2.8 Hz), 8.81 (1H,d, J=2.0 Hz).

Step 2: Preparation of1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one

To a suspension of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (70mg, 0.028 mmol),1-(5-bromopyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one (105mg, 0.310 mmol) and Cs₂CO₃ (270 mg, 0.829 mmol) in dioxane (2 mL) wasadded Pd₂(dba)₃ (25 mg, 0.028 mmol) and Brettphos (30 mg, 0.055 mmol)under N₂ atmosphere. Then the mixture was stirred at about 100° C. for16 h. A brown suspension was formed. LCMS showed1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one was consumedcompletely and the purity of desired product (Rt=0.720 min; MS Calc'd:511.2; MS Found: 512.1 [M+H]⁺). The mixture was filtered and the cakewas washed with DCM/MeOH (10:1, 5 mL×3). The combined filtrate wasconcentrated to dryness. The residue was purified by prep-HPLC (0.225%FA as an additive). After lyophilization, the product was trituratedwith EtOAc (2 mL) and filtered. The cake was lyophilized for 16 h togive1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one(13.06 mg, 8% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.04-2.14 (2H, m), 2.53-2.54 (2H, m), 3.49-3.57 (2H, m), 3.85-3.92 (4H,m), 4.57 (2H, s), 6.97 (1H, d, J=8.4 Hz), 7.60-7.80 (5H, m), 7.93-7.98(1H, m), 8.30-8.35 (1H, m), 8.50 (1H, t, J=2.4 Hz), 8.54 (1H, d, J=2.4Hz), 8.66 (1H, d, J=1.2 Hz), 9.12 (1H, d, J=2.0 Hz), 9.41 (1H, br s).

Example 164:1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one

To a suspension of 1-(4-(5-aminopyrazin-2-yl)phenyl)pyrrolidin-2-one (70mg, 0.28 mmol),1-(5-bromopyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one (105mg, 0.310 mmol) and Cs₂CO₃ (269 mg, 0.826 mmol) in dioxane (2 mL) wasadded Pd₂(dba)³ (25 mg, 0.028 mmol) Brettphos (30 mg, 0.055 mmol) underN₂ atmosphere. Then the mixture was stirred at about 100° C. for 16 h. Abrown suspension was formed. LCMS showed desired product purity(Rt=0.716 min; MS Calc'd: 512.2; MS Found: 513.1 [M+H]⁺). The mixturewas filtered and the cake was washed with DCM/MeOH (10:1, 5 mL×3). Thecombined filtrate was concentrated to dryness. The residue was purifiedby prep-HPLC (0.225% FA as an additive). After lyophilization, theproduct was triturated with EtOAc (2 mL) and filtered. The cake waslyophilized for 16 h to give1-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)pyridin-3-yl)-3-(thiazol-4-ylmethyl)imidazolidin-2-one(8.46 mg, 5% yield) as an off-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.04-2.14 (2H, m), 2.53-2.54 (2H, m), 3.49-3.57 (2H, m), 3.85-3.94 (4H,m), 4.58 (2H, s), 7.85 (1H, d, J=2.0 Hz), 7.78 (2H, d, J=8.8 Hz), 8.04(2H, d, J=8.8 Hz), 8.34-8.38 (2H, m), 8.55 (1H, t, J=2.4 Hz), 8.69 (1H,d, J=2.0 Hz), 8.79 (1H, d, J=1.2 Hz), 9.12 (1H, d, J=2.0 Hz), 9.87 (1H,br s).

Example 165:1-(oxazol-4-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

Step 1: Preparation of oxazol-4-ylmethanol

To a solution of ethyl oxazole-4-carboxylate (2.00 g, 14.2 mmol in THF(20 mL)/H₂O (3 mL) was added NaBH₄ (1.07 g, 28.3 mmol) at 0° C. and thenthe mixture was stirred at 25° C. for 72 h. A white cloudy was formed.To the mixture was added anhydrous Na₂SO₄ (20 g) and the mixture wasstirred at 25° C. for 1 hour. The mixture was filtered and the cake waswashed with MTBE (20 mL). The combined organic layer was concentrated todryness. The residue was purified by Combi Flash (EtOAc in pentane from10% to 100%) to give oxazol-4-ylmethanol (800 mg, 56% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.52 (1H, brt, J=5.6 Hz), 4.64(2H, d, J=5.6 Hz), 7.64 (1H, d, J=0.8 Hz), 7.89 (1H, s).

Step 2: Preparation of oxazol-4-ylmethyl 4-methylbenzenesulfonate

To a solution of oxazol-4-ylmethanol (150 mg, 1.51 mmol) and Ts₂O (544mg, 1.67 mmol) in DCM (5 mL) was added TEA (383 mg, 3.78 mmol) at 0° C.and then the mixture was stirred at 0° C. for 1 hour. A yellow solutionwas formed. TLC (EtOAc, by KMnO₄) showed oxazol-4-ylmethanol wasconsumed completely and a new spot (Rf˜0.8) was formed. The mixture waspoured into water (10 mL) and extracted with DCM (5 mL×2). The combinedorganic layer was washed with brine (10 mL), dried over Na₂SO₄ andconcentrated to dryness to give oxazol-4-ylmethyl4-methylbenzenesulfonate (400 mg, crude) as yellow oil, which was usedto next step directly.

Step 3: Preparation of1-(5-bromopyridin-3-yl)-3-(oxazol-4-ylmethyl)imidazolidin-2-one

To a solution of 1-(5-bromopyridin-3-yl)imidazolidin-2-one (130 mg,0.537 mmol) in DMF (2 mL) was added NaH (64 mg, 1.6 mmol, 60% purity) at0° C. and then the mixture was stirred at 25° C. for 30 min. To themixture was added oxazol-4-ylmethyl 4-methylbenzenesulfonate (400 mg,crude) at 0° C. and the mixture was stirred at 25° C. for 1 hour. Ayellow suspension was formed. LCMS showed1-(5-bromopyridin-3-yl)imidazolidin-2-one was consumed completely andthe purity of desired product (Rt=0.680 min; MS Calc'd: 322.0; MS Found:324.6 [M+H]⁺). The mixture was poured into sat.aq.NH₄Cl (50 mL) andextracted with EtOAc (50 mL×3). The combined organic layer was washedwith brine (50 mL×6), dried over Na₂SO₄ and concentrated to dryness. Theresidue was purified by Combi Flash (eluting with EtOAc in pentane from10% to 100%). to give1-(5-bromopyridin-3-yl)-3-(oxazol-4-ylmethyl)imidazolidin-2-one (150 mg,86% yield) as a yellow gum. ¹H NMR (400 MHz, CDCl₃) δ 3.60-3.70 (2H, m),3.80-3.90 (2H, m), 4.44 (2H, s), 7.70 (1H, s), 7.88 (1H, s), 8.32-8.36(1H, m), 8.43-8.47 (1H, m), 8.49-8.54 (1H, m).

Step 4: Preparation of1-(oxazol-4-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

To a suspension of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (70mg, 0.28 mmol),1-(5-bromopyridin-3-yl)-3-(oxazol-4-ylmethyl)imidazolidin-2-one (100 mg,0.310 mmol) and Cs₂CO₃ (270 mg, 0.829 mmol) in dioxane (2 mL) was addedPd₂(dba)₃ (25 mg, 0.028 mmol) and Brettphos (30 mg, 0.055 mmol) under N₂atmosphere. Then the mixture was stirred at about 100° C. for 16 h. Abrown suspension was formed. LCMS showed purity of desired product(Rt=0.683 min; MS Calc'd: 495.2; MS Found: 496.1[M+H]⁺). The mixture wasfiltered and the cake was washed with DCM/MeOH (10:1, 10 mL×3). Thecombined filtrate was concentrated to dryness. The residue was purifiedby prep-HPLC (0.05% ammonia hydroxide as an additive) and thenlyophilization to give1-(oxazol-4-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(33.6 mg, 24% yield) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.00-2.14 (2H, m), 2.53-2.54 (2H, m),3.45-3.53 (2H, m), 3.80-3.90 (4H, m), 4.33 (2H, s), 6.97 (1H, d, J=8.8Hz), 7.66 (2H, d, J=8.8 Hz), 7.72 (2H, d, J=8.8 Hz), 7.94 (1H, dd,J=8.8, 2.8 Hz), 8.06 (1H, d, J=0.8 Hz), 8.29 (1H, d, J=2.4 Hz), 8.33(1H, d, J=0.8 Hz), 8.49 (1H, d, J=2.4 Hz), 8.51 (1H, d, J=2.4 Hz), 8.58(1H, d, J=2.4 Hz).

Example 166:1-(oxazol-5-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

Step 1: Preparation of oxazol-5-ylmethanol

To a solution of ethyl oxazole-5-carboxylate (2.00 g, 14.2 mmol) in THF(20 mL) was added NaBH₄ (1.07 g, 28.3 mmol) at 0° C. and then themixture was stirred at 25° C. for 48 h. A white cloudy was formed. Tothe mixture was added anhydrous Na₂SO₄ (20 g) and the mixture wasstirred at 25° C. for 1 hour. The mixture was filtered and the cake waswashed with MTBE (20 mL). The combined organic layer was concentrated todryness. The residue was purified by Combi Flash (EtOAc in pentane from10% to 100%) to give oxazol-5-ylmethanol (900 mg, 64% yield) ascolorless oil. ¹H NMR (400 MHz, CDCl₃) δ 2.02 (1H, brt, J=6.0 Hz), 4.74(2H, d, J=6.0 Hz), 7.06 (1H, s), 7.89 (1H, s).

Step 2: Preparation of oxazol-5-ylmethyl 4-methylbenzenesulfonate

To a solution of oxazol-5-ylmethanol (150 mg, 1.51 mmol) and Ts₂O (519mg, 1.59 mmol) in DCM (5 mL) was added TEA (383 mg, 3.78 mmol) at 0° C.and then the mixture was stirred at 0° C. for 1 hour. A yellow solutionwas formed. TLC (EtOAc, by KMnO₄) showed oxazol-5-ylmethanol wasconsumed completely and a new spot (Rf˜0.8) was formed. The mixture waspoured into water (10 mL) and extracted with DCM (5 mL×2). The combinedorganic layer was washed with brine (10 mL), dried over Na₂SO₄ andconcentrated to dryness to give oxazol-5-ylmethyl4-methylbenzenesulfonate (400 mg, crude) as yellow oil, which was usedto next step directly.

Step 3: Preparation of1-(5-bromopyridin-3-yl)-3-(oxazol-5-ylmethyl)imidazolidin-2-one

To a solution of 1-(5-bromopyridin-3-yl)imidazolidin-2-one (150 mg,0.620 mmol) in DMF (5 mL) was added NaH (75 mg, 1.9 mmol, 60% purity) at0° C. and then the mixture was stirred at 25° C. for 30 min. To themixture was added oxazol-5-ylmethyl 4-methylbenzenesulfonate (400 mg,crude) at 0° C. and the mixture was stirred at 25° C. for 1 hour. Abrown suspension was formed. LCMS showed about 14% of1-(5-bromopyridin-3-yl)imidazolidin-2-one (Rt=0.585 min; MS Calc'd:241.0; MS Found: 241.8 [M+H]⁺) was remained and purity of desiredproduct was 46% (Rt=0.683 min; MS Calc'd: 322.0; MS Found: 324.8[M+H]⁺).To the mixture was added oxazol-5-ylmethyl 4-methylbenzenesulfonate (200mg crude) at 0° C. and then the mixture was stirred at 25° C. for 1hour. A brown suspension was formed. LCMS showed desired product purity(Rt=0.693 min; MS Calc'd: 322.0; MS Found: 322.7[M+H]⁺). The mixture waspoured into sat.aq.NH₄Cl (10 mL) and extracted with EtOAc (10 mL×3). Thecombined organic layer was washed with brine (10 mL×6), dried overNa₂SO₄ and concentrated to dryness. The residue was purified by CombiFlash (EtOAc=100%) to give1-(5-bromopyridin-3-yl)-3-(oxazol-5-ylmethyl)imidazolidin-2-one (150 mg,74% yield) as an off-white solid. ¹H NMR (400 MHz, CDCl₃) δ 3.54-3.61(2H, m), 3.84-3.93 (2H, m), 4.59 (2H, s), 7.10 (1H, s), 7.90 (1H, s),8.38 (1H, d, J=1.6 Hz), 8.47 (1H, t, J=2.4 Hz), 8.54 (1H, d, J=2.4 Hz).

Step 4: Preparation of1-(oxazol-5-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

To a suspension of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (80mg, 0.32 mmol),1-(5-bromopyridin-3-yl)-3-(oxazol-5-ylmethyl)imidazolidin-2-one (114 mg,0.354 mmol) and Cs₂CO₃ (309 mg, 0.948 mmol) in dioxane (2 mL) was addedPd₂(dba)₃ (29 mg, 0.032 mmol) and Brettphos (34 mg, 0.063 mmol) under N₂atmosphere. Then the mixture was stirred at about 100° C. for 16 h. Abrown suspension was formed. LCMS showed desired purity of product(Rt=0.683 min; MS Calc'd: 495.2; MS Found: 496.1[M+H]⁺). The mixture wasfiltered and the cake was washed with DCM/MeOH (10:1, 10 mL×3). Thecombined filtrate was concentrated to dryness. The residue was purifiedby prep-HPLC (0.05% ammonia hydroxide as an additive) and thenlyophilized to give1-(oxazol-5-ylmethyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(8.1 mg, 5% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ2.04-2.14 (2H, m), 2.53-2.54 (2H, m), 3.44-3.51 (2H, m), 3.80-3.91 (4H,m), 4.53 (2H, s), 6.97 (1H, d, J=8.8 Hz), 7.19 (1H, s), 7.68 (2H, d,J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 7.94 (1H, dd, J=8.8, 2.8 Hz), 8.31(1H, d, J=2.4 Hz), 8.37 (1H, s), 8.49 (1H, d, J=2.4 Hz), 8.53 (1H, d,J=2.8 Hz), 8.67 (1H, d, J=2.4 Hz), 9.41 (1H, br s).

Example 167:(E)-4-(4-(dimethylamino)but-2-enamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide

A solution of1-(4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(100 mg, 0.290 mmol), (E)-4-(4-(dimethylamino)but-2-enamido)benzoic acid(143 mg, 0.579 mmol) and EDCI (138 mg, 0.724 mmol) in pyridine (5 mL)was stirred at 25° C. under N₂ for 3 hours. LCMS showed that the purityof desired product is 68.9%. The reaction mixture was stirred at 25° C.under N₂ for 30 min. A yellow suspension was formed. LCMS showed thatthe starting material was consumed completely. The purity of desiredproduct is 93% (Rt=0.591 min; MS Calcd: 575.3; MS Found: 576.1 [M+H]⁺).The reaction mixture was concentrated to dryness. The residue wastriturated with MeCN/MeOH (1/1, 10 mL) and filtered to give an impureproduct (84 mg). The impure product was triturated with MeCN (10 mL) togive(E)-4-(4-(dimethylamino)but-2-enamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide(71.3 mg, yield: 42.8%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.10-2.27 (2H, m), 2.56-2.59 (2H, m), 2.79(6H, brs), 3.89 (2H, t, J=6.6 Hz), 3.96 (2H, brs), 6.56 (1H, d, J=14.4Hz), 6.81-6.93 (1H, m), 7.12 (1H, d, J=8.4 Hz), 7.69-7.74 (2H, m),7.75-7.80 (2H, m), 7.90 (2H, d, J=8.4 Hz), 8.07 (2H, d, J=8.4 Hz), 8.63(1H, brs), 8.79 (1H, brs), 8.96 (1H, brs), 9.13 (1H, brs), 10.25 (1H,brs), 10.59 (1H, brs), 10.86 (1H, brs), 10.92 (1H, brs).

Example 168:4-(4-(dimethylamino)butanamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide

A mixture of1-(4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(50 mg, 0.15 mmol, HCl salt) and 4-(4-(dimethylamino)butanamido)benzoicacid (72 mg, 0.29 mmol) in pyridine (3 mL) was added EDCI (56 mg, 0.29mmol) at 28° C., then the reaction mixture was stirred at 28° C. for 5.5hours. A yellow solution was formed. LCMS showed that the purity ofdesired product is 94.8% (Rt=0.562; MS Calcd: 577.2; MS Found: 578.1[M+H]⁺). The reaction mixture was concentrated to dryness. Then theresidue was purified by prep-HPLC (0.1% TFA as an additive) andlyophilized to give4-(4-(dimethylamino)butanamido)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)benzamide(7.7 mg, yield: 8.9%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.90-2.01 (2H, m), 2.05-2.15 (2H, m),2.53-2.56 (4H, m), 2.82 (6H, d, J=5.2 Hz), 3.08-3.16 (2H, m), 3.85-3.91(2H, t, J=7.2 Hz), 7.02-7.07 (1H, m), 7.68-7.73 (2H, m), 7.75-7.79 (4H,m), 7.99-8.05 (3H, m), 8.59 (1H, d, J=2.0 Hz), 8.65 (1H, d, J=16.8 Hz),8.85 (1H, s), 8.93 (1H, brs), 9.86 (1H, brs), 10.38 (1H, brs), 10.61(1H, brs).

Example 169:(E)-4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)but-2-enamide

Step 1: Preparation of tert-butyl(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)carbamate

To a mixture of1-(4-(6-((5-aminopyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(300 mg, 0.717 mmol, HCl salt) and3-(3-((tert-butoxycarbonyl)amino)phenyl)propanoic acid (209 mg, 0.789mmol) in pyridine (10 mL) was added EDCI (275 mg, 1.43 mmol) at 28° C.and then the reaction mixture was stirred at 50° C. for 2 hours. Ayellow suspension was formed. LCMS showed that purity of product is 82%(Rt=0.784 min; MS Calcd: 592.2; MS Found: 593.3 [M+H]⁺). The mixture wasadded water (20 mL) and extracted with EtOAc (50 mL×3). Then organiclayer was concentrated to dryness. The aqueous layer was extracted withDCM/MeOH (10/1, 50 mL×3). The combined organic layer was concentratedunder reduced pressure to give tert-butyl(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)carbamate(500 mg, crude) as a yellow solid.

Step 2: Preparation of3-(3-aminophenyl)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)propanamide

A suspension of tert-butyl(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)carbamate(500 mg, 0.844 mmol, crude) in HCl/EtOAc (35 mL, 4 M in EtOAc) wasstirred at 28° C. for 1 hour. A yellow suspension was formed. LCMSshowed that the purity of desired product is 98.8% (Rt=0.672 min; MSCalcd: 492.2; MS Found: 493.3 [M+H]⁺). The mixture was concentrated todryness. The residue was triturated with sat.NaHCO₃ (10 mL)/MeCN (5 mL)and filtered. The filter cake was triturated with MeCN (5 mL) to give3-(3-aminophenyl)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)propanamide(230 mg, yield for two steps: 65%) as a light red solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.06-2.13 (2H, m), 2.64-2.65 (2H, m),2.74-2.85 (2H, m), 2.93-2.98 (2H, m), 3.89 (2H, t, J=6.8 Hz), 6.95-7.15(4H, m), 7.24-7.41 (1H, m), 7.67-7.84 (4H, m), 8.06 (1H, d, J=7.2 Hz),8.61 (2H, d, J=8.4 Hz), 8.69 (1H, s), 9.04 (1H, s), 10.16 (1H, brs),10.80 (1H, brs).

Step 3: Preparation of(E)-4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)but-2-enamide

To a mixture of3-(4-aminophenyl)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)propanamide(50 mg, 0.10 mmol) and (E)-4-(dimethylamino)but-2-enoic acid (26 mg,0.20 mmol) in pyridine (2 mL) was added EDCI (39 mg, 0.20 mmol) at 28°C. and then the reaction mixture was stirred at 28° C. for 3 hours. Ared suspension was formed. LCMS showed that the purity of desiredproduct is 69% (Rt=1.254 min; MS Calcd: 603.3; MS Found: 604.2 [M+H]⁺).The reaction mixture was concentrated to dryness. Then the residue waspurified by prep-HPLC (0.225% FA as an additive) and lyophilized to give(E)-4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)but-2-enamide(15.5 mg, yield: 24%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.11 (2H, m), 2.49 (6H, s), 2.48-2.51(2H, m), 2.65-2.70 (2H, m), 2.84-2.95 (2H, m), 3.54-3.62 (2H, m), 3.87(2H, t, J=6.8 Hz), 6.36 (1H, d, J=15.6 Hz), 6.63-6.78 (1H, m), 6.97 (1H,t, J=8.8 Hz), 7.25 (1H, t, J=7.6 Hz), 7.49 (1H, d, J=8.0 Hz), 7.59 (1H,s), 7.65-7.71 (2H, m), 7.73-7.76 (2H, m), 7.95 (1H, dd, J=8.4 Hz, 2.4Hz), 8.14 (1H, s), 8.33 (1H, d, J=2.0 Hz), 8.48-8.55 (2H, m), 8.61 (1H,d, J=2.0 Hz), 9.4 (1H, s), 10.11 (1H, s), 10.15 (1H, s).

Example 170:4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)butanamide

To a mixture of3-(4-aminophenyl)-N-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)propanamide(50 mg, 0.10 mmol) and 4-(dimethylamino)butanoic acid (27 mg, 0.20 mmol)in pyridine (2 mL) was added EDCI (39 mg, 0.20 mmol) at 28° C. and thenthe reaction mixture was stirred at 28° C. for 16 hours. A redsuspension was formed. LCMS showed that the purity of desired product is92% (Rt=1.244 min; MS Calcd: 605.3; MS Found: 606.3[M+H]⁺). The reactionmixture was concentrated to dryness. Then the residue was purified byprep-HPLC (0.225% FA as an additive) and lyophilized to give4-(dimethylamino)-N-(3-(3-oxo-3-((5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)amino)propyl)phenyl)butanamide(7.0 mg, yield: 11%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.85-1.95 (2H, m), 2.03-2.15 (2H, m),2.37-2.42 (2H, in), 2.46-2.50 (2H, m), 2.65-2.71 (4H, m), 2.79 (6H, s),2.85-2.95 (2H, m), 3.87 (2H, t, J=7.2 Hz), 6.94-7.00 (2H, m), 7.22 (1H,t, J=9.6 Hz), 7.40 (1H, d, J=8.0 Hz), 7.52 (1H, s), 7.65-7.71 (2H, m),7.72-7.78 (2H, m), 7.98 (1H, dd, J=8.8, 2.4 Hz), 8.43 (1H, s), 8.54 (1H,d, J=2.4 Hz), 8.57 (1H, brs), 8.74 (1H, s), 9.64 (1H, brs), 9.96 (1H,s), 10.3 (1H, brs).

Example 171:(E)-4-(dimethylamino)-N-(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide

Step 1: Preparation of1-(3-nitrobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

A suspension of1-(5-bromopyridin-3-yl)-3-(3-nitrobenzyl)imidazolidin-2-one (830 mg,2.20 mmol), 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (615 mg,2.43 mmol), Pd₂(dba)₃ (202 mg, 0.220 mmol), Brettphos (236 mg, 0.440mmol) and Cs₂CO₃ (2.15 g, 6.60 mmol) in dioxane (20 mL) was stirred at100° C. for 16 hours under N₂ atmosphere. A black suspension was formed.LCMS showed the purity of the desired product is 28% (Rt=0.799 min; MSCalcd: 549.1; MS Found: 550.1 [M+H]⁺). The reaction mixture was dilutedwith water (10 mL) and EtOAc/THF (40 mL, 1/1) then separated. Theaqueous was extracted with EtOAc/THF (50 mL×3, 1/1) and then extractedwith DCM (50 mL×3). The combined organic phase was concentrated. Theresidue was purified by Combi Flash (4% MeOH in DCM) and triturated withPE/EtOAc (15 mL, 1/1) to give1-(3-nitrobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(500 mg, yield: 41%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.15 (2H, m), 2.55-2.63 (2H, overlappedwith DMSO), 3.48 (2H, t, J=7.6 Hz), 3.81-3.97 (4H, m), 4.58 (2H, s),6.98 (1H, d, J=7.8 Hz), 7.64-7.78 (5H, m), 7.82 (1H, d, J=10.8 Hz), 7.95(1H, d, J=7.2 Hz), 8.13-8.27 (2H, m), 8.35 (1H, s), 8.53 (2H, d, J=6.4Hz), 8.70 (1H, s), 9.44 (1H, brs).

Step 2: Preparation of1-(3-aminobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

A mixture of1-(3-nitrobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(450 mg, 0.819 mol) and Pd/C (300 mg, 10% purity, 50% wet) in THF (500mL) was stirred at 25° C. for 16 hours under H₂ balloon (15 Psi). Ablack suspension was formed. LCMS showed the purity of the desiredproduct is 59% (Rt=0.659 min; MS Calcd: 519.2; MS Found: 520.3 [M+H]⁺).The reaction mixture was filtered and the filter cake was washed withTHF/DCM (50 mL×6, 1/1). The combined organic phase was concentrated. Theresidue was purified by Combi Flash (10% MeOH in DCM) to give1-(3-aminobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(250 mg, yield: 59%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.12 (2H, m), 2.52-2.55 (2H, overlappedwith DMSO), 3.39 (2H, t, J=7.4 Hz), 3.83-3.89 (4H, m), 4.26 (2H, s),5.10 (2H, brs), 6.42-6.50 (3H, m), 6.94-7.02 (2H, m), 7.64-7.78 (4H, m),7.94 (1H, dd, J=8.8 Hz, 2.8 Hz), 8.34 (1H, d, J=2.4 Hz), 8.48 (1H, t,J=2.4 Hz), 8.53 (1H, d, J=2.4 Hz), 8.67 (1H, d, J=2.4 Hz), 9.39 (1H,brs).

Step 3: Preparation of tert-butyl(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)carbamate

A mixture of1-(3-aminobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(250 mg, 0.481 mmol), Boc-gly-OH (126 mg, 0.722 mol) and EDCI (190 mg,0.991 mmol) in pyridine (4 mL) was stirred at 20° C. for 2 hours. Abrown solution was formed. LCMS showed the purity of the desired productis 84% (Rt=1.084 min; MS Calcd: 676.3; MS Found: 677.3 [M+H]⁺). Thereaction mixture was diluted with DCM (20 mL) and water (10 mL) thenseparated. The aqueous was extracted with DCM (20 mL×3). The combinedorganic phase was concentrated to give tert-butyl(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)carbamate(380 mg, crude) as a yellow solid, which used for next step withoutpurification.

Step 4: Preparation of2-amino-N-(3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide

A mixture of tert-butyl(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)carbamate(380 mg, 0.562 mol) in HCl/dioxane (40 mL, 4M in dioxane) was stirred at20° C. for 2 hours. The reaction mixture turned into white suspensionfrom yellow solution. LCMS showed the purity of the desired product is100% (Rt=0.928 min; MS Calcd: 576.1; MS Found: 577.1 [M+H]⁺). Thereaction mixture was concentrated. The residue was washed with saturatedaqueous NaHCO₃ (15 mL) and filtered to give2-amino-N-(3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide(400 mg, crude) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.12 (2H, m), 2.55-2.58 (2H, overlappedwith DMSO), 3.22-3.30 (2H, m), 3.41-3.44 (2H, overlapped with H₂O),3.81-3.92 (4H, m), 4.39 (2H, s), 6.92-7.04 (2H, m), 7.30 (1H, t, J=7.6Hz), 7.53-7.63 (2H, m), 7.64-7.78 (4H, m), 7.94 (1H, d, J=8.4 Hz),8.30-8.37 (1H, m), 8.43-8.51 (1H, m), 8.52-8.54 (1H, m), 8.66 (1H, s),9.39 (1H, brs).

Step 5: Preparation of(E)-4-(dimethylamino)-N-(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide

A mixture of2-amino-N-(3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide(100 mg, 0.173 mmol), (E)-4-(dimethylamino)but-2-enoic acid (27 mg,0.209 mmol), EDCI (55 mg, 0.285 mmol), HOBt (36 mg, 0.269 mmol) and TEA(53 mg, 0.520 mmol) in DMF (3 mL) was stirred at 25° C. for 16 hoursunder N₂ atmosphere. A black suspension was formed. LCMS showed thepurity of the desired product is 100% (Rt=1.607 min; MS Calcd: 687.3; MSFound: 688.3 [M+H]⁺). The reaction mixture was filtered. The filtratedwas purified by prep-HPLC (0.04% NH₃H₂O+10 mM NH₄HCO₃ as additives),lyophilized and triturated with MeCN/PE (0.5 mL, 1/1) to give(E)-4-(dimethylamino)-N-(2-oxo-2-((3-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide(5.3 mg, yield: 4%) as a gray brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.12 (2H, m), 2.26 (6H, s), 2.52-2.55(2H, overlapped with DMSO), 3.03-3.25 (2H, m), 3.41 (2H, t, J=7.6 Hz),3.83-3.90 (4H, m), 3.95 (2H, d, J=5.6 Hz), 4.39 (2H, s), 6.18 (1H, d,J=15.6 Hz), 6.54-6.61 (1H, m), 6.94-7.03 (2H, m), 7.31 (1H, t, J=8.0Hz), 7.52-7.59 (2H, m), 7.65-7.77 (4H, m), 7.95 (1H, dd, J=8.4 Hz, 2.4Hz), 8.34 (1H, d, J=2.4 Hz), 8.38-8.45 (1H, m), 8.47-8.52 (1H, m),8.53-8.55 (1H, m), 8.65-8.69 (1H, m), 9.39 (1H, brs), 10.08 (1H, s).

Example 172:(E)-4-(dimethylamino)-N-(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide

Step 1: Preparation of tert-butyl(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)carbamate

To a mixture of 1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (200mg, 0.790 mmol) in dioxane (6 mL) was added tert-butyl(4-((3-(5-bromopyridin-3-yl)-2-oxoimidazolidin-1-yl)methyl)phenyl)carbamate(424 mg, 0.948 mmol), Pd(dba)₂ (45 mg, 0.079 mmol), Brettphos (42 mg,0.079 mmol) and Cs₂CO₃ (514 mg, 1.58 mmol), the reaction mixture waspurged in N₂ atmosphere for 3 times and stirred at 50° C. for 1 hour,then heated to 100° C. under N₂ atmosphere and stirred for another 5hours to give a yellow suspension. LCMS showed the purity of the desiredproduct is 50% (Rt=0.816 min; MS Calcd: 619.3; MS Found: 620.2 [M+H]⁺).The mixture was cooled to room temperature and diluted with water (40mL). Some yellow solid was precipitated out and filtered. The filtercake was dried in high vacuum to give a residue. The residue was washedwith EtOAc (30 mL) twice to give tert-butyl(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)carbamate(400 mg, yield: 82%) as a red solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.47 (9H, s), 2.02-2.13 (2H, m), 2.49-2.53(2H, m), 3.34-3.40 (2H, m), 3.82-3.91 (4H, m), 4.34 (2H, s), 6.97 (1H,d, J=8.4 Hz), 7.20 (2H, d, J=8.4 Hz), 7.44 (2H, d, J=8.4 Hz), 7.69 (2H,d, J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz), 7.95 (1H, dd, J=8.8, 2.4 Hz), 8.33(1H, d, J=2.0 Hz), 8.48 (1H, t, J=2.4 Hz), 8.54 (1H, d, J=2.4 Hz), 8.68(1H, d, J=2.0 Hz), 9.36 (1H, brs), 9.39 (1H, brs).

Step 2: Preparation of1-(4-aminobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one

To a mixture of tert-butyl(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)carbamate(400 mg, 0.645 mmol) in EtOAc (5 mL) was added HCl/EtOAc (20 mL, 4M inEtOAc), the resulting mixture was stirred at 25° C. for 3 hours to givean off-white suspension. LCMS showed the purity of product is 95%(Rt=0.688 min; MS Calcd: 519.2; MS Found: 520.1 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give1-(4-aminobenzyl)-3-(5-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(350 mg, crude, HCl salt) as an off-white solid.

Step 3: Preparation of tert-butyl(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)carbamate

To a mixture of1-(4-aminobenzyl)-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-2-one(150 mg, 0.270 mmol, HCl salt) in DMF (8 mL) was added Boc-gly-OH (236mg, 1.35 mmol), and HOBt (73 mg, 0.54 mmol), EDCI (103 mg, 0.540 mmol)and TEA (82 mg, 0.81 mmol), the reaction mixture was stirred at 100° C.and stirred for 6 hours to give a brown suspension. LCMS showed thepurity of the desired product is 52% (Rt=0.797 min; MS Calcd: 676.3; MSFound: 677.1 [M+H]⁺). The mixture was diluted with water (30 mL) andextracted with DCM (35 mL×3). The combined organic layer was washed withbrine (50 mL×2), dried over anhydrous Na₂SO₄ and concentrated underreduced pressure to give a residue. The residue was washed with EtOAc(20 mL) twice to give (180 mg, yield for two steps: 96%) as an off-whitesolid.

Step 4: Preparation of2-amino-N-(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide

To a mixture of tert-butyl(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)carbamate(180 mg, 0.266 mmol) in EtOAc (10 mL) was added HCl/EtOAc (20 mL, 4 M inEtOAc), the reaction mixture was stirred at 25° C. for 2 hours to givean off-white suspension. LCMS showed the purity of product is 48%(Rt=0.710 min; MS Calcd: 576.3; MS Found: 577.1 [M+H]⁺). The mixture wasconcentrated under reduced pressure to give2-amino-N-(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide(160 mg, crude, HCl salt) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.13 (2H, m), 2.49-2.53 (2H, m), 3.49(2H, t, J=8.0 Hz), 3.75-3.84 (2H, m), 3.85-3.96 (4H, m), 4.43 (2H, s),7.15 (1H, d, J=8.4 Hz), 7.32 (2H, d, J=8.4 Hz), 7.63 (2H, d, J=8.4 Hz),7.72 (2H, d, J=8.8 Hz), 7.77 (2H, d, J=8.8 Hz), 8.08 (1H, dd, J=8.4, 2.4Hz), 8.27 (2H, brs), 8.65 (1H, d, J=2.4 Hz), 8.69 (1H, d, J=2.0 Hz),8.74 (1H, d, J=2.0 Hz), 9.25 (1H, d, J=1.6 Hz), 10.72 (1H, brs), 10.81(1H, brs).

Step 4: Preparation of(E)-4-(dimethylamino)-N-(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide

To a mixture of2-amino-N-(4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)acetamide(150 mg, 0.245 mmol, HCl salt) in DMF (5 mL) was added(E)-4-(dimethylamino)but-2-enoic acid (122 mg, 0.734 mmol, HCl salt),EDCI (141 mg, 0.734 mmol), HOBt (99 mg, 0.73 mmol) and TEA (99 mg, 0.98mmol), the reaction mixture was stirred at 25° C. for 2 hours to give abrown suspension. LCMS showed the purity of the desired product is 63%(Rt=1.621 min; MS Calcd: 687.3; MS Found: 688.1 [M+H]⁺). The mixture wasdiluted with water (30 mL) and DCM (30 mL) and then filtered. The filtercake was washed with DCM/MeOH (10:1, 11 mL×2). The filtrate wasextracted with DCM (40 mL×2), the combined extracts were washed withbrine (50 mL×2), dried over Na₂SO₄, filtered and concentrated underreduced pressure to give a residue. The residue was washed with DMF togive an impure product (60 mg). Then further purified by prep-HPLC(0.225% FA as an additive) purification to give(E)-4-(dimethylamino)-N-(2-oxo-2-((4-((2-oxo-3-(5-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)pyridin-3-yl)imidazolidin-1-yl)methyl)phenyl)amino)ethyl)but-2-enamide(5.4 mg, yield for two steps: 3%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.13 (2H, m), 2.36 (6H, s), 2.49-2.53(2H, m), 3.31-3.42 (2H, m), 3.42-3.48 (2H, m), 3.82-3.90 (4H, m),3.94-4.02 (2H, m), 4.36 (2H, s), 6.23 (1H, d, J=15.6 Hz), 6.52-6.65 (1H,m), 6.96 (1H, d, J=8.8 Hz), 7.26 (2H, d, J=8.0 Hz), 7.58 (2H, d, J=8.0Hz), 7.67 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8 Hz), 7.94 (1H, dd,J=8.4, 2.4 Hz), 8.32 (1H, s), 8.42-8.49 (2H, m), 8.52 (1H, d, J=2.0 Hz),8.66 (1H, brs), 9.40 (1H, brs), 10.08 (1H, brs).

Example 173:(R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of 1-(4-(6-chloropyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(150 mg, 0.516 mmol),(R)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(138 mg, 0.670 mmol), Pd₂(dba)₃ (47 mg, 0.051 mmol), Brettphos (55 mg,0.10 mmol) and Cs₂CO₃ (336 mg, 1.03 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. Then the resulting reactionmixture was heated at 90° C. for 15 hours under N₂ atmosphere. Thereaction mixture turned into yellow suspension from red. Crude LCMSshowed the purity of the desired product is 22% (Rt=0.569 min; MS Calcd:459.4; MS Found: 460.0 [M+H]⁺). The reaction mixture was diluted withwater (20 mL) and EtOAc (20 mL). The aqueous layer was extracted withEtOAc/THF (20 mL×3, 1/1). The combined organic layer was washed withbrine (25 mL), dried over anhydrous Na₂SO₄ and concentrated. The residuewas purified by Combi Flash (2% to 5% MeOH in DCM) and triturated withCH₃CN (5 mL) to give a impure product and lyophilized to give(R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(39.3 mg, yield: 17%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.71 (1H, t, J=6.0 Hz), 2.14 (2H, t, J=7.2Hz), 2.21-2.25 (1H, m), 2.35-2.42 (1H, m), 2.44-2.47 (2H, m), 2.64-2.74(1H, m), 3.79 (2H, t, J=6.8 Hz), 3.91 (1H, t, J=10.8 Hz), 4.03-4.12 (1H,m), 4.59 (1H, dd, J=10.8, 2.8 Hz), 6.88 (1H, d, J=8.8 Hz), 7.46-7.56(2H, m), 7.60 (1H, d, J=10.8 Hz), 7.94 (1H, dd, J=8.8, 2.4 Hz), 8.44(1H, d, J=2.4 Hz), 8.51 (1H, d, J=2.4 Hz), 8.97 (1H, d, J=2.8 Hz), 9.29(1H, brs).

Example 174:1-(4-(6-((5-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Preparation of tert-butyl(N-(2-chloroethyl)-N-methylsulfamoyl)carbamate

To a solution of chlorosulfonyl isocyanate (2.50 g, 17.7 mmol) inanhydrous DCM (25 mL) was added t-BuOH (1.69 mL, 17.7 mmol) dropwise at0° C. After stirring at 0° C. for 0.5 hour, the resultingN-Boc-sulfamoyl chloride and TEA (5.36 g, 53.0 mmol) solution was addeddropwise to a solution of 2-chloro-N-methylethan-1-amine-HCl (2.30 g,17.7 mmol) in DCM (60 mL) at 0-5° C. After the completion of theaddition, the reaction mixture was stirred at 0-5° C. for 0.5 hour, thenfurther stirred at 20-25° C. for 2 hours. The reaction mixture turnedinto yellow suspension from solution. The reaction mixture was dilutedwith DCM (250 mL), then washed with 1N aqueous HCl (100 mL), brine (100mL), dried over anhydrous Na₂SO₄ and concentrated. The residue waspurified by Combi Flash (10% to 25% EtOAc in PE) to give tert-butyl(N-(2-chloroethyl)-N-methylsulfamoyl)carbamate (4.50 g, yield: 93%) asyellow oil.

¹H NMR (400 MHz, CDCl₃) δ 1.50 (9H, s), 3.05 (3H, s), 3.68 (4H, s), 7.12(1H, brs).

Step 2: Preparation of tert-butyl5-methyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide

A mixture of tert-butyl (N-(2-chloroethyl)-N-methylsulfamoyl)carbamate(4.00 g, 14.7 mmol) and K₂CO₃ (3.04 g, 22.0 mmol) in DMSO (40 mL) wasstirred at 15-20° C. for 16 hours. The reaction mixture turned intowhite suspension from colorless solution. To the reaction mixture wasadded water (100 mL), then extracted with EtOAc (100 mL×3). The combinedorganic layer was washed with water (100 mL×2), brine (100 mL), driedover anhydrous Na₂SO₄ and concentrated. The residue was purified byCombi Flash (10% to 25% EtOAc in PE) to give tert-butyl5-methyl-1,2,5-thiadiazolidine-2-carboxylate 1,1-dioxide (2.80 g, yield:81%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 1.55 (9H, s), 2.78 (3H, s), 3.31 (2H, t, J=6.4Hz), 3.81 (2H, t, J=6.4 Hz).

Step 3: Preparation of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide

To a solution of tert-butyl 5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (2.30 g, 9.73 mmol) in anhydrous DCM (25 mL) was added TFA(25 mL) at 15-20° C. Then the reaction mixture was stirred at 15-20° C.for 1 hour. The reaction turned into pale yellow solution fromcolorless. The reaction mixture was concentrated and the residue wasdiluted with DCM (50 mL) and basified with DIPEA to pH=8 andconcentrated. The residue was purified by Combi Flash (10% to 50% EtOAcin PE) to give 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (1.15 g,yield: 87%) as colorless oil.

¹H NMR (400 MHz, CDCl₃) δ 2.75 (3H, s), 3.36-341 (2H, m), 3.48-3.53 (2H,m), 4.47 (1H, brs).

Step 4: Preparation of2-(5-bromopyridin-3-yl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide

A mixture of 2-methyl-1,2,5-thiadiazolidine 1,1-dioxide (50 mg, 0.37mmol), 3, 5-dibromopyridine (261 mg, 1.10 mmol), CuI (21 mg, 0.11 mmol),Cs₂CO₃ (179 mg, 0.550 mmol) and DMEDA (19 mg, 0.22 mmol) in anhydrousdioxane (4 mL) was degassed and purged with N₂ for 3 times. Then theresulting reaction mixture was heated at 100° C. for 16 hours under N₂atmosphere. The reaction mixture turned into blue suspension fromyellow. LCMS showed the purity of the desired product is 31% (Rt=0.692min; MS Calcd: 291.0; MS Found: 291.6 [M+H]⁺). The reaction mixture wasfiltered and the filtrate was concentrated. The residue was purified byCombi Flash (20% to 60% EtOAc in PE) to give2-(5-bromopyridin-3-yl)-5-methyl-1,2,5-thiadiazolidine 1,1-dioxide (58mg, yield: 54%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.88 (3H, s), 3.53-3.58 (2H, m), 3.87 (2H, t,J=6.4 Hz), 7.81 (1H, t, J=2.4 Hz), 8.39 (1H, d, J=2.4 Hz), 8.46 (1H, d,J=2.0 Hz).

Step 5: Preparation of1-(4-(6-((5-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 2-(5-bromopyridin-3-yl)-5-methyl-1,2,5-thiadiazolidine1,1-dioxide (58 mg, 0.20 mmol),1-(4-(6-aminopyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg, 0.20 mmol),Pd₂(dba)₃ (9 mg, 0.01 mmol), Brettphos (11 mg, 0.020 mmol) and Cs₂CO₃(129 mg, 0.395 mmol) in anhydrous dioxane (3 mL) was degassed and purgedwith N₂ for 3 times. Then the reaction mixture was heated at 100° C. for16 hours under N₂ atmosphere. The reaction mixture turned into brownsuspension from red. LCMS showed the purity of the desired product is75% (Rt=0.744 min; MS Calcd: 464.2; MS Found: 465.0 [M+H]⁺). To thereaction mixture was added water (20 mL), then extracted with EtOAc/THF(20 mL×3, 1/1). The combined organic layer was washed with brine (20mL), dried over anhydrous Na₂SO₄ and concentrated. The residue wastriturated with EtOAc (5 mL), then further purified by prep-HPLC (0.225%FA as an additive). Most of the CH₃CN was removed under reduced pressureand the remaining part was lyophilized to give1-(4-(6-((5-(5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)pyridin-3-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(12.6 mg, yield: 14%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.00-2.15 (2H, m), 2.52-2.55 (2H, m), 2.76(3H, s), 3.54 (2H, t, J=6.4 Hz), 3.88 (2H, t, J=7.2 Hz), 3.93 (2H, t,J=6.4 Hz), 6.98 (1H, d, J=8.4 Hz), 7.69 (2H, d, J=9.2 Hz), 7.75 (2H, d,J=8.8 Hz), 7.95-8.05 (1H, m), 8.21 (1H, t, J=2.0 Hz), 8.54 (1H, d, J=2.4Hz), 8.76 (1H, s), 9.59 (1H, brs).

Example 175:(S)-1-(4-(6-((2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

Step 1: Preparation of (R)-1-(benzyloxy)-3-(methylamino)propan-2-ol

A solution of (S)-2-((benzyloxy)methyl)oxirane (6.00 g, 36.5 mmol) inDCM (25 mL) was added dropwise to MeNH₂ (130 mL, 40% purity in MeOH) at0° C. After the addition, the reaction mixture was stirred at 10-15° C.for 16 hours. The reaction mixture turned into suspension from solution.The reaction mixture was concentrated and the remaining part wasextracted with DCM (100 mL×3). The combined organic layer was washedwith brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated to give(R)-1-(benzyloxy)-3-(methylamino)propan-2-ol (6.10 g, yield: 86%) asyellow oil.

¹H NMR (400 MHz, CDCl₃) δ 2.44 (3H, s), 2.65-2.70 (2H, m), 3.45-3.55(2H, m), 3.90-3.95 (1H, m), 4.55 (2H, s), 7.25-7.40 (5H, m).

Step 2: Preparation of methyl(S)-3-((benzyloxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide

To a solution of (R)-1-(benzyloxy)-3-(methylamino)propan-2-ol (6.10 g,31.2 mmol) in anhydrous THF (200 mL) was added Burgess reagent (18.6 g,78.1 mmol) at 10-15° C. Then the reaction mixture was stirred at 75° C.for 16 hours. The reaction mixture turned into yellow solution fromcolorless. To the reaction mixture was added saturated aqueous NH₄Cl(100 mL), then extracted with EtOAc (200 mL×2). The combined organiclayer was washed with brine (100 mL), dried over anhydrous Na₂SO₄ andconcentrated. The residue was purified by Combi Flash (10% to 30% EtOAcin PE) to give methyl(S)-3-((benzyloxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (5.92 g, yield: 60%) as yellow gum.

¹H NMR (400 MHz, CDCl₃) δ 2.77 (3H, s), 3.33-3.39 (1H, m), 3.41-3.45(1H, m), 3.64-3.69 (1H, m), 3.74-3.79 (1H, m), 3.90 (3H, s), 4.24-4.31(1H, m), 4.52-4.60 (2H, m), 7.29-7.40 (5H, m).

Step 3: Preparation of methyl(S)-3-(hydroxymethyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide

To a solution of methyl(S)-3-((benzyloxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (5.92 g, 18.8 mmol) in absolute MeOH (200 mL) was added 10%Pd(OH)₂/C (1.00 g) under N₂ atmosphere. The reaction mixture wasdegassed and purged with H₂ for 3 times and the resulting reactionmixture was hydrogenated (50 psi) at 50° C. for 24 hours. The reactionmixture turned into colorless from yellow solution. The reaction mixturewas filtered and the solid was washed with MeOH (10 mL×3). The filtratewas concentrated and the residue was dissolved in EtOH (25 mL) andconcentrated to give methyl(S)-3-(hydroxymethyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (3.50 g, yield: 83%) as colorless gum.

¹H NMR (400 MHz, CDCl₃) δ 2.80 (3H, s), 3.35-3.45 (2H, m), 3.75-3.85(2H, m), 3.93 (3H, s), 4.20-4.30 (1H, m).

Step 4: Preparation of methyl(S)-3-(((3-bromo-5-nitropyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide

A mixture of methyl(S)-3-(hydroxymethyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (3.30 g, 14.7 mmol), 3-bromo-2-chloro-5-nitro-pyridine (4.19g, 17.7 mmol) and K₂CO₃ (4.07 g, 29.4 mmol) in CH₃CN (60 mL) was heatedat 90° C. for 2 hours under N₂ atmosphere. The reaction mixture turnedinto brown suspension from yellow. The reaction mixture was filtered andthe solid was washed with EtOAc (20 mL×3). The filtrate was concentratedand the residue was purified by Combi Flash (20% to 40% EtOAc in PE) togive methyl(S)-3-(((3-bromo-5-nitropyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (4.20 g, yield: 67%) as yellow gum.

Step 5: Preparation of methyl(S)-3-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide and(S)-3-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-1,2,512-thiadiazolidine1,1-dioxide

A mixture of methyl(S)-3-(((3-bromo-5-nitropyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (4.20 g, 9.88 mmol) and Fe powder (2.21 g, 39.5 mmol), NH₄Cl(5.28 g, 98.8 mmol) in EtOH (45 mL) and H₂O (15 mL) was heated at 90° C.for 16 hours. The reaction mixture turned into black suspension fromgray. The reaction mixture was filtered through a pad of celite and thesolid was washed with EtOH (20 mL×3). The filtrate was concentrated andthe residue was diluted with water (50 mL) and extracted with EtOAc (50mL×3). The combined organic layer was washed with brine (50 mL), driedover anhydrous Na₂SO₄ and concentrated. The residue was purified byCombi Flash (50% to 100% EtOAc in PE) to give methyl(S)-3-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (2.40 g, yield: 61%) as a yellow solid and(S)-3-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-1,2,512-thiadiazolidine1,1-dioxide (860 mg, yield: 26%) as a gray solid.

Step 6: Preparation of methyl(S)-3-(((3-bromo-5-((di-tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate-1,1-dioxide

To a solution of methyl(S)-3-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (3.20 g, 8.10 mmol), DIPEA (4.19 g, 32.4 mmol) and DMAP (198mg, 1.62 mmol) in DCM (80 mL) was added Boc₂O (7.07 g, 32.4 mmol) at15-20° C. Then the reaction mixture was stirred at 15-20° C. for 16hours under N₂ atmosphere. The reaction mixture turned into yellowsolution from colorless. The reaction mixture was concentrated and theresidue was purified by Combi Flash (30% to 80% EtOAc in PE) to give(S)-3-(((3-bromo-5-((di-tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate-1,1-dioxide(2.20 g, yield: 46%) as yellow gum.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (18H, s), 2.80 (3H, s), 3.15-3.25 (1H,m), 3.70-3.80 (4H, m), 4.25-4.35 (2H, m), 5.30-5.35 (1H, m), 7.84 (1H,d, J=2.0 Hz), 8.21 (1H, d, J=2.4 Hz).

Step 7: Preparation of tert-butyl(S)-3-(((3-bromo-5-((di-tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide

To a solution of(S)-4-(((5-amino-3-bromopyridin-2-yl)oxy)methyl)-2-methyl-1,2,5-thiadiazolidine1,1-dioxide (860 mg, 2.55 mmol), DIPEA (1.32 g, 10.2 mmol) and DMAP (62mg, 0.51 mmol) in DCM (25 mL) was added Boc₂O (2.23 g, 10.2 mmol) at15-20° C. Then the reaction mixture was stirred at 15-20° C. for 16hours under N₂ atmosphere. The reaction mixture turned into yellowsolution from colorless. The reaction mixture was concentrated and theresidue was purified by Combi Flash (20% to 50% EtOAc in PE) to givetert-butyl(S)-3-(((3-bromo-5-((di-tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (1.50 g, yield: 92%) as colorless gum.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (27H, s), 2.79 (3H, s), 3.20-3.25 (1H,m), 3.75-3.80 (1H, m), 4.20-4.25 (2H, m), 5.25-5.30 (1H, m), 7.84 (1H,d, J=2.4 Hz), 8.22 (1H, d, J=2.0 Hz).

Step 8: Preparation of tert-butyl(S)-(5-bromo-6-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methoxy)pyridin-3-yl)carbamate

To a solution of tert-butyl(S)-3-(((3-bromo-5-((di-tert-butoxycarbonyl)amino)pyridin-2-yl)oxy)methyl)-5-methyl-1,2,5-thiadiazolidine-2-carboxylate1,1-dioxide (2.20 g, 3.69 mmol) in MeOH (40 mL) and H₂O (20 mL) wasadded 10% aqueous NaOH (10 mL) at 15-20° C. Then the reaction mixturewas stirred at 15-20° C. for 2 hours. The reaction mixture turned intoyellow solution from colorless. The reaction mixture was concentrated.The residue was diluted with water (50 mL), then extracted with EtOAc(50 mL×3). The combined organic layer was washed with brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby Combi Flash (30% to 80% EtOAc in PE) to give tert-butyl(S)-(5-bromo-6-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methoxy)pyridin-3-yl)carbamate(2.00 g) as colorless gum. The average yield was 46% for 3 steps.

¹H NMR (400 MHz, CDCl₃) δ 1.55 (9H, s), 2.27 (1H, dd, J=7.6, 5.6 Hz),2.84 (3H, s), 3.34-3.40 (1H, m), 3.62-3.70 (3H, m), 4.82-4.90 (1H, m),6.68 (1H, s), 8.29 (1H, d, J=2.8 Hz), 8.44 (1H, s).

Step 9: Preparation of tert-butyl(S)-(2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)carbamate

A mixture of tert-butyl(S)-(5-bromo-6-((5-methyl-1,1-dioxido-1,2,5-thiadiazolidin-3-yl)methoxy)pyridin-3-yl)carbamate(2.30 g, 5.26 mmol), CuI (301 mg, 1.58 mmol), Cs₂CO₃ (3.43 g, 10.5 mmol)and DMEDA (278 mg, 3.16 mmol) in anhydrous dioxane (80 mL) was degassedand purged with N₂ for 3 times. Then the resulting reaction mixture washeated at 90° C. for 16 hours under N₂ atmosphere. The reaction mixtureturned into brown suspension from yellow. LCMS showed the purity of thedesired product is 74% (Rt=0.754 min; MS Calcd: 356.1; MS Found: 379.2[M+Na]+). The reaction mixture was filtered through a pad of celite andthe solid was washed with EtOAc (25 mL×4). The filtrate was concentratedand the residue was purified by Combi Flash (35% to 70% EtOAc in PE),then further purified by YMC-Pack CN (0% to 80% EtOH in PE) to givetert-butyl(S)-(2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)carbamate(560 mg, yield: 30%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.51 (9H, s), 2.89 (3H, s), 3.24 (1H, dd,J=10.4, 5.4 Hz), 3.60 (1H, dd, J=10.0, 4.8 Hz), 3.85 (1H, t, J=10.8 Hz),4.15-4.23 (1H, m), 4.34 (1H, dd, J=10.8, 3.2 Hz), 8.52 (1H, brs),7.82-7.86 (2H, m).

Step 10: Preparation of(S)-8-amino-2-methyl-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazine1,1-dioxide

To a solution of tert-butyl(S)-(2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)carbamate(560 mg, 1.57 mmol) in anhydrous DCM (5 mL) was added TFA (5 mL) at15-20° C. Then the reaction mixture was stirred at 15-20° C. for 2hours. The reaction mixture turned into yellow solution from colorless.The reaction mixture was concentrated and the residue was basified withsaturated aqueous NaHCO₃ to pH=8, then extracted with DCM (15 mL×5). Thecombined organic layer was dried over anhydrous Na₂SO₄ and concentratedto give(S)-8-amino-2-methyl-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazine1,1-dioxide (339 mg, yield: 84%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.80 (3H, s), 3.15 (1H, dd, J=10.4, 4.8 Hz),3.52 (1H, dd, J=10.4, 7.2 Hz), 3.83 (1H, t, J=10.8 Hz), 4.00-4.10 (1H,m), 4.18 (1H, dd, J=10.8, 3.2 Hz), 6.56 (1H, d, J=2.4 Hz), 7.60 (1H, d,J=2.4 Hz).

Note: Two protons of NH₂ were not observed.

Step 11: Preparation of(S)-1-(4-(6-((2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of(S)-8-amino-2-methyl-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazine1,1-dioxide (60 mg, 0.23 mmol),1-(4-(6-chloropyridin-3-yl)phenyl)pyrrolidin-2-one (77 mg, 0.28 mmol),Pd₂(dba)₃ (21 mg, 0.023 mmol), Brettphos (25 mg, 0.047 mmol) and Cs₂CO₃(229 mg, 0.702 mmol) in anhydrous dioxane (3 mL) was degassed and purgedwith N₂ for 3 times. Then the resulting reaction mixture was heated at90° C. for 16 hours. The reaction mixture turned into brown suspensionfrom red. LCMS showed the purity of the desired product is 70% (Rt=1.079min; MS Calcd: 492.2; MS Found: 493.1 [M+H]⁺). The mixture was filteredthrough a pad of celite and the solid was washed with DCM/MeOH (10 mL×4,10/1) and the filtrate was concentrated. The residue was purified byCombi Flash (2% to 10% MeOH in DCM), then triturated with CH₃CN (5 mL)and lyophilized to give(S)-1-(4-(6-((2-methyl-1,1-dioxido-2,3,3a,4-tetrahydropyrido[2,3-b][1,2,5]thiadiazolo[2,3-d][1,4]oxazin-8-yl)amino)pyridin-3-yl)phenyl)pyrrolidin-2-one(24.9 mg, yield: 22%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.03-2.13 (2H, m), 2.55-2.60 (2H, m), 2.74(3H, s), 3.25-3.30 (1H, m), 3.60 (1H, dd, J=10.8, 6.8 Hz), 3.70 (1H, t,J=6.8 Hz), 3.87 (2H, t, J=6.8 Hz), 4.20-4.30 (1H, m), 4.49 (1H, dd,J=10.8, 2.8 Hz), 6.92 (1H, d, J=8.8 Hz), 7.67 (2H, d, J=8.8 Hz), 7.74(2H, d, J=8.8 Hz), 7.94 (1H, dd, J=8.8, 2.4 Hz), 8.16 (2H, s), 8.52 (1H,d, J=2.4 Hz), 9.43 (1H, brs).

Example 176:(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(500 mg, 1.74 mmol), 5-bromo-2-chloro-4-methylpyridine (359 mg, 1.74mmol), Pd(dppf)Cl₂ (127 mg, 0.174 mmol) and Na₂CO₃ (554 mg, 5.22 mmol)in dioxane (6 mL) and water (1.5 mL) was degassed and purged with N₂ for3 times. And the resulting reaction mixture was stirred at 100° C. for 2hours under N₂ atmosphere. A black suspension was formed. LCMS showedthe purity of the desired product is 52% (Rt=0.858 min; MS Calcd: 286.1;MS Found: 287.0 [M+H]⁺). The reaction mixture was diluted with water (10mL). The aqueous layer was extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with water (20 mL×2), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combi Flash (20% to 60% EtOAc in PE) to give1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (450 mg,yield: 79%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.16-2.25 (2H, m), 2.28 (3H, s), 2.65 (2H, t,J=8.2 Hz), 3.92 (2H, t, J=7.0 Hz), 7.24 (1H, s), 7.27-7.32 (2H, m),7.69-7.75 (2H, m), 8.19 (1H, s).

Step 2: Preparation of(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of 1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one(50 mg, 0.17 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(36 mg, 0.17 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol), Brettphos (19 mg,0.034 mmol) and Cs₂CO₃ (114 mg, 0.348 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A graysuspension was formed. LCMS showed the purity of the desired product is56% (Rt=0.722 min; MS Calcd: 455.2; MS Found: 456.1[M+H]+). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (0.225% FA as an additive) to give(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(15.1 mg, yield: 19%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.76 (1H, m), 2.05-2.10 (2H, m),2.19-2.26 (4H, m), 2.35-2.43 (1H, m), 2.50-2.56 (2H, m), 2.63-2.74 (1H,m), 3.86-3.94 (3H, m), 4.04-4.10 (1H, m), 4.59 (1H, dd, J=10.8 Hz, 3.0Hz), 6.74 (1H, s), 7.37 (2H, d, J=8.6 Hz), 7.73 (2H, d, J=8.6 Hz), 7.92(1H, s), 8.37 (1H, d, J=2.4 Hz), 8.93 (1H, d, J=2.4 Hz), 9.19 (1H, brs).

Example 177:(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 2-(5-bromo-2-chloropyridin-4-yl)propan-2-ol

To a solution of methyl 5-bromo-2-chloroisonicotinate (2.00 g, 7.98mmol) in THF (20 mL) was added MeMgBr (6.6 mL, 3 M in THF) dropwise at−10° C. The resulting reaction mixture was warmed to 0° C. gradually andfurther stirred for 2 hours under N₂ atmosphere. A yellow suspension wasformed. TLC showed the starting material was consumed completely. Thereaction mixture was quenched with sat. aq. NH₄Cl (20 mL), and extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 50% EtOAc in PE) to give2-(5-bromo-2-chloropyridin-4-yl)propan-2-ol (1.60 g, yield: 80%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ1.73 (6H, s), 2.49 (1H, brs), 7.75 (1H, s),8.43 (1H, s).

Step 2: Preparation of 5-bromo-2-chloro-4-isopropylpyridine

A solution of 2-(5-bromo-2-chloropyridin-4-yl)propan-2-ol (500 mg, 2.00mmol) in HI (20 mL, 40%) was stirred at 100° C. for 48 hours. A blacksolution with black deposit was formed. TLC showed the starting materialwas consumed completely. The reaction mixture was quenched withsat.aq.Na₂SO₃ (10 mL), and extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with sat. aq. Na₂SO₃ (20 mL×2), brine (40 mL),dried over anhydrous Na₂SO₄, filtered and concentrated under reducedpressure. The residue was purified by Combi Flash (0% to 10% EtOAc inPE) to give 5-bromo-2-chloro-4-isopropylpyridine (468 mg, yield: 61%) ascolorless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (6H, d, J=6.8 Hz), 3.25-3.30 (1H, m),7.22 (1H, s), 8.42 (1H, s).

Step 3: Preparation of1-(4-(6-chloro-4-isopropylpyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-isopropylpyridine (163 mg, 0.696 mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(200 mg, 0.696 mmol), Pd(dppf)Cl₂ (51 mg, 0.070 mmol) and Na₂CO₃ (221mg, 2.09 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 100° C. for 2 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 41%(Rt=0.931 min; MS Calcd: 314.1; MS Found: 315.0 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 60% EtOAc in PE) to give1-(4-(6-chloro-4-isopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (200 mg,yield: 64%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.15 (6H, d, J=6.8 Hz), 2.16-2.25 (2H, m),2.61-2.69 (2H, m), 3.01-3.12 (1H, m), 3.89-3.94 (2H, m), 7.24 (1H, s),7.27-7.30 (2H, m), 7.69-7.73 (2H, m), 8.16 (1H, s).

Step 4: Preparation of compound(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-isopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (200 mg,0.635 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(130 mg, 0.635 mmol), Pd₂(dba)₃ (58 mg, 0.063 mmol), Brettphos (68 mg,0.127 mmol) and Cs₂CO₃ (414 mg, 1.27 mmol) in anhydrous dioxane (8 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A graysuspension was formed. LCMS showed the purity of the desired product is39% (Rt=0.757 min; MS Calcd: 483.2; MS Found: 484.2[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (0% to 10% MeOH in DCM) to give a crude compound(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(200 mg, crude, contained byproduct(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)-4-(prop-1-en-2-yl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one)as a yellow solid, which was further treated with H₂ (45 psi)/Pd/C. Theresidue was purified by prep-HPLC (0.225% FA as an additive) to give(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(52.8 mg, yield: 17% for 2 steps) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.11 (6H, d, J=6.8 Hz), 1.65-1.76 (1H, m),2.05-2.13 (2H, m), 2.18-2.26 (1H, m), 2.35-2.43 (1H, m), 2.50-2.56 (2H,m), 2.63-2.70 (1H, m), 2.95-3.02 (1H, m), 3.86-3.94 (3H, m), 4.04-4.10(1H, m), 4.58 (1H, dd, J=10.8 Hz, 3.0 Hz), 6.83 (1H, s), 7.31 (2H, d,J=8.6 Hz), 7.73 (2H, d, J=8.6 Hz), 7.86 (1H, s), 8.36 (1H, d, J=2.4 Hz),8.95 (1H, d, J=2.4 Hz), 9.18 (1H, brs).

Example 178:(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 5-bromo-2-chloro-4-iodopyridine

To a solution of 5-bromo-2-chloropyridine (2.00 g, 10.4 mmol) inanhydrous THF (40 mL) was added LDA (6.2 mL, 2 M in THF) dropwise at−60° C. After the addition, the resulting reaction mixture was stirredat −60° C. for 0.5 h. Then NIS (2.34 g, 10.4 mmol) was added into abovesolution in portions at −60° C. The reaction mixture was warmed to 15°C. gradually and further stirred for 1.5 hours under N₂ atmosphere. Ayellow solution was formed. TLC showed the starting material wasconsumed completely. The reaction mixture was quenched with sat. aq.NH₄Cl (20 mL), then extracted with EtOAc (30 mL×3). The combined organiclayer was washed with water (20 mL×2), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combi Flash (0% to 10% EtOAc in PE) to give5-bromo-2-chloro-4-iodopyridine (2.00 g, yield: 60%) as a white solid.¹H NMR (400 MHz, CDCl₃) δ 7.86 (1H, s), 8.47 (1H, s).

Step 2: Preparation of 5-bromo-2-chloro-4-cyclopropylpyridine

A mixture of 5-bromo-2-chloro-4-iodopyridine (200 mg, 0.628 mmol),cyclopropylboronic acid (54 mg, 0.63 mmol), Pd(dppf)Cl₂ (46 mg, 0.063mmol) and Na₂CO₃ (200 mg, 1.88 mmol) in dioxane (4 mL) and water (1 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 100° C. for 16 hours under N₂ atmosphere. A blacksuspension was formed. LCMS showed the purity of the desired product is52% (Rt=0.931 min; MS Calcd: 230.9; MS Found: 231.6 [M+H]⁺). Thereaction mixture was diluted with water (10 mL). The aqueous layer wasextracted with EtOAc (30 mL×3). The combined organic layer was washedwith water (20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by Combi Flash (0% to 10% EtOAc in PE) to give5-bromo-2-chloro-4-cyclopropylpyridine (122 mg, yield: 64%) as a yellowsolid.

Step 3: Preparation of1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-cyclopropylpyridine (81 mg, 0.35 mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(100 mg, 0.348 mmol), Pd(dppf)Cl₂ (25 mg, 0.035 mmol) and Na₂CO₃ (111mg, 1.04 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 100° C. for 2 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 54%(Rt=0.721 min; MS Calcd: 312.1; MS Found: 312.8 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 50% EtOAc in PE) to give1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (100mg, yield: 92%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 0.82-0.88 (2H, m), 1.02-1.07 (2H, m),1.87-1.92 (1H, m), 2.17-2.25 (2H, m), 2.66 (2H, t, J=8.2 Hz), 3.92 (2H,t, J=7.0 Hz), 6.76 (1H, s), 7.40-7.44 (2H, m), 7.71-7.75 (2H, m), 8.16(1H, s).

Step 4: Preparation of(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (100mg, 0.320 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(66 mg, 0.32 mmol), Pd₂(dba)₃ (29 mg, 0.032 mmol), Brettphos (34 mg,0.064 mmol) and Cs₂CO₃ (208 mg, 0.639 mmol) in anhydrous dioxane (5 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS showed the purity of the desired product is58% (Rt=0.747 min; MS Calcd: 481.2; MS Found: 482.1[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith DCM/MeOH (30 mL×3, 10/1). The combined organic layer was washedwith water (20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by Combi Flash (0% to 10% MeOH in DCM), and further purified byprep-HPLC (0.225% FA as an additive) to give(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(40.0 mg, yield: 26%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.70-0.79 (2H, m), 0.94-1.01 (2H, m),1.64-1.75 (1H, m), 1.77-1.84 (1H, m), 2.05-2.11 (2H, m), 2.17-2.24 (1H,m), 2.34-2.43 (1H, m), 2.50-2.56 (2H, m), 2.63-2.73 (1H, m), 3.85-3.93(3H, m), 4.02-4.10 (1H, m), 4.57 (1H, dd, J=10.8 Hz, 3.0 Hz), 6.35 (1H,s), 7.44 (2H, d, J=8.6 Hz), 7.74 (2H, d, J=8.6 Hz), 7.91 (1H, s), 8.37(1H, d, J=2.4 Hz), 8.93 (1H, d, J=2.6 Hz), 9.04 (1H, brs).

Example 179:(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-methoxypyridin-3-yl)phenyl)pyrrolidin-2-one

A mixture of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(500 mg, 1.74 mmol), 5-bromo-2-chloro-4-methoxypyridine (387 mg, 1.74mmol), Pd(dppf)Cl₂ (127 mg, 0.174 mmol) and Na₂CO₃ (554 mg, 5.22 mmol)in dioxane (6 mL) and water (1.5 mL) was degassed and purged with N₂ for3 times. And the resulting reaction mixture was stirred at 100° C. for 2hours under N₂ atmosphere. A black suspension was formed. LCMS showedthe purity of the desired product is 51% (Rt=0.649 min; MS Calcd: 302.1;MS Found: 302.8 [M+H]⁺). The reaction mixture was diluted with water (10mL). The aqueous layer was extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with water (20 mL×2), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combi Flash (20% to 60% EtOAc in PE) to give1-(4-(6-chloro-4-methoxypyridin-3-yl)phenyl)pyrrolidin-2-one (450 mg,yield: 78%) as a yellow solid.

Step 2: Preparation of(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-methoxypyridin-3-yl)phenyl)pyrrolidin-2-one (50 mg,0.17 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(34 mg, 0.17 mmol), Pd₂(dba)₃ (15 mg, 0.017 mmol), Brettphos (18 mg,0.033 mmol) and Cs₂CO₃ (108 mg, 0.330 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A graysuspension was formed. LCMS showed the purity of the desired product is60% (Rt=0.721 min; MS Calcd: 471.2; MS Found: 472.1[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (0% to 10% MeOH in DCM), and further purified by prep-HPLC (0.225%FA as an additive) to give(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(57.1 mg, yield: 67%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.76 (1H, m), 2.04-2.10 (2H, m),2.19-2.26 (1H, m), 2.33-2.43 (1H, m), 2.50-2.56 (2H, m), 2.63-2.73 (1H,m), 3.80-3.94 (6H, m), 4.04-4.11 (1H, m), 4.59 (1H, dd, J=10.6 Hz, 3.0Hz), 6.48 (1H, s), 7.47 (2H, d, J=8.8 Hz), 7.68 (2H, d, J=8.8 Hz), 7.95(1H, s), 8.39 (1H, d, J=2.4 Hz), 8.94 (1H, d, J=2.4 Hz), 9.26 (1H, brs).

Example 180:(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-methylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-methylpyridine (203 mg, 0.983 mmol),1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(300 mg, 0.983 mmol), Pd(dppf)Cl₂ (72 mg, 0.098 mmol) and Na₂CO₃ (313mg, 2.95 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 90° C. for 4 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 60%(Rt=0.850 min; MS Calcd: 304.1; MS Found: 304.9 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 80% EtOAc in PE) to give1-(4-(6-chloro-4-methylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(240 mg, yield: 80%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.21-2.28 (2H, m), 2.30 (3H, s), 2.61 (2H, t,J=8.0 Hz), 3.89 (2H, t, J=7.0 Hz), 7.07-7.12 (2H, m), 7.24-7.26 (1H, m),7.52-7.56 (1H, m), 8.19 (1H, s).

Step 2: Preparation of(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-methylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one (50mg, 0.16 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(34 mg, 0.16 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Brettphos (18 mg,0.033 mmol) and Cs₂CO₃ (107 mg, 0.328 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS showed the purity of the desired product is54% (Rt=0.717 min; MS Calcd: 455.2; MS Found: 456.1[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (0.225% FA as an additive) to give(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(41.2 mg, yield: 52%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.76 (1H, m), 2.09-2.17 (2H, m),2.17-2.23 (1H, m), 2.24 (3H, s), 2.35-2.43 (1H, m), 2.43-2.50 (2H, m),2.62-2.72 (1H, m), 3.80 (2H, t, J=7.0 Hz), 3.88-3.94 (1H, m), 4.04-4.10(1H, m), 4.59 (1H, dd, J=10.8 Hz, 3.0 Hz), 6.74 (1H, s), 7.21-7.27 (1H,m), 7.32-7.38 (1H, m), 7.50 (1H, t, J=8.2 Hz), 7.96 (1H, s), 8.37 (1H,d, J=2.4 Hz), 8.92 (1H, d, J=2.4 Hz), 9.24 (1H, brs).

Example 181:(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-isopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-isopropylpyridine (154 mg, 0.655 mmol),1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(200 mg, 0.655 mmol), Pd(dppf)Cl₂ (48 mg, 0.065 mmol) and Na₂CO₃ (208mg, 1.97 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 100° C. for 2 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 37%(Rt=0.895 min; MS Calcd: 332.1; MS Found: 332.9 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 60% EtOAc in PE) to give1-(4-(6-chloro-4-isopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(170 mg, yield: 55%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.18 (6H, d, J=6.8 Hz), 2.20-2.29 (2H, m),2.58-2.63 (2H, m), 3.00-3.10 (1H, m), 3.87-3.94 (2H, m), 7.05-7.10 (1H,m), 7.17-7.21 (1H, m), 7.24-7.26 (1H, m), 7.31 (1H, s), 8.16 (1H, s).

Step 2: Preparation of(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-isopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(170 mg, 0.511 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(105 mg, 0.511 mmol), Pd₂(dba)₃ (47 mg, 0.051 mmol), Brettphos (55 mg,0.102 mmol) and Cs₂CO₃ (326 mg, 1.02 mmol) in dioxane (8 mL) wasdegassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A graysuspension was formed. LCMS the purity of the desired product is 30%(Rt=0.761 min; MS Calcd: 501.2; MS Found: 502.1 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (0% to 10% MeOH in DCM) to give a crude compound(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(180 mg, crude, contained byproduct(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-(prop-1-en-2-yl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one)as a yellow solid, which was further treated with H₂ (45 psi)/Pd/C. Theresidue was purified by prep-HPLC (0.225% FA as an additive) to give(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(28.9 mg, yield: 11% for 2 steps) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.13 (6H, d, J=6.8 Hz), 1.64-1.76 (1H, m),2.10-2.17 (2H, m), 2.18-2.23 (1H, m), 2.35-2.43 (1H, m), 2.46 (2H, t,J=8.0 Hz), 2.62-2.72 (1H, m), 2.93-3.01 (1H, m), 3.81 (2H, t, J=6.8 Hz),3.86-3.94 (1H, m), 4.04-4.11 (1H, m), 4.58 (1H, dd, J=10.8 Hz, 3.0 Hz),6.83 (1H, s), 7.15-7.21 (1H, m), 7.25-7.32 (1H, m), 7.51 (1H, t, J=8.2Hz), 7.91 (1H, s), 8.37 (1H, d, J=2.4 Hz), 8.95 (1H, d, J=2.4 Hz), 9.18(1H, brs).

Example 182:(S)-2-((4-cyclopropyl-5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-cyclopropylpyridine (122 mg, 0.524mmol),1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(160 mg, 0.524 mmol), Pd(dppf)Cl₂ (38 mg, 0.052 mmol) and Na₂CO₃ (167mg, 1.57 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 100° C. for 2 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 40%(Rt=0.694 min; MS Calcd: 330.1; MS Found: 330.8 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 60% EtOAc in PE) to give1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(112 mg, yield: 39%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 0.83-0.88 (2H, m), 1.06-1.09 (2H, m),1.87-1.93 (1H, m), 2.20-2.30 (2H, m), 2.58-2.64 (2H, m), 3.90 (2H, t,J=7.0 Hz), 6.77 (1H, s), 7.20-7.24 (1H, m), 7.32-7.43 (1H, m), 7.52-7.60(1H, m), 8.15 (1H, s).

Step 2: Preparation of(S)-2-((4-cyclopropyl-5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(100 mg, 0.302 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(62 mg, 0.30 mmol), Pd₂(dba)₃ (28 mg, 0.030 mmol), Brettphos (32 mg,0.060 mmol) and Cs₂CO₃ (197 mg, 0.604 mmol) in anhydrous dioxane (5 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS showed the purity of the desired product is42% (Rt=0.750 min; MS Calcd: 499.2; MS Found: 500.2 [M+H]⁺). Thereaction mixture was diluted with water (10 mL). The aqueous layer wasextracted with DCM/MeOH (30 mL×3, 10/1). The combined organic layer waswashed with water (20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄,filtered and concentrated under reduced pressure. The residue waspurified by Combi Flash (0% to 5% MeOH in DCM), and further purified byprep-HPLC (0.225% FA as an additive) and prep-HPLC (0.05% NH₃.H₂O as anadditive) to give(S)-2-((4-cyclopropyl-5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(12.1 mg, yield: 8%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.73-0.80 (2H, m), 0.97-1.03 (2H, m),1.64-1.75 (1H, m), 1.79-1.87 (1H, m), 2.10-2.21 (3H, m), 2.35-2.43 (1H,m), 2.46 (2H, t, J=8.0 Hz), 2.63-2.73 (1H, m), 3.81 (2H, t, J=7.0 Hz),3.86-3.94 (1H, m), 4.04-4.11 (1H, m), 4.57 (1H, dd, J=10.8 Hz, 3.0 Hz),6.37 (1H, s), 7.29-7.33 (1H, m), 7.36-7.41 (1H, m), 7.52 (1H, t, J=8.2Hz), 7.95 (1H, s), 8.37 (1H, d, J=2.4 Hz), 8.92 (1H, d, J=2.6 Hz), 9.09(1H, brs).

Example 183:(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methoxypyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-4-methoxypyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one

A mixture of 5-bromo-2-chloro-4-methoxypyridine (219 mg, 0.983 mmol),1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(300 mg, 0.983 mmol), Pd(dppf)Cl₂ (72 mg, 0.098 mmol) and Na₂CO₃ (313mg, 2.95 mmol) in dioxane (4 mL) and water (1 mL) was degassed andpurged with N₂ for 3 times. And the resulting reaction mixture wasstirred at 90° C. for 4 hours under N₂ atmosphere. A black suspensionwas formed. LCMS showed the purity of the desired product is 63%(Rt=0.823 min; MS Calcd: 320.1; MS Found: 320.9 [M+H]). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (20% to 80% EtOAc in PE) to give1-(4-(6-chloro-4-methoxypyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(230 mg, yield: 78%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.20-2.28 (2H, m), 2.60 (2H, t, J=8.0 Hz),3.84-3.89 (2H, m), 3.90 (3H, s), 6.92 (1H, s), 7.24-7.33 (2H, m), 7.49(1H, t, J=8.0 Hz), 8.19 (1H, s).

Step 2: Preparation of(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methoxypyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloro-4-methoxypyridin-3-yl)-2-fluorophenyl)pyrrolidin-2-one(50 mg, 0.16 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(32 mg, 0.16 mmol), Pd₂(dba)₃ (14 mg, 0.016 mmol), Brettphos (17 mg,0.032 mmol) and Cs₂CO₃ (101 mg, 0.311 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting reactionmixture was stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS showed the purity of the desired product is58% (Rt=0.716 min; MS Calcd: 489.2; MS Found: 490.1[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified by CombiFlash (0% to 10% MeOH in DCM), and further purified by prep-TLC(DCM/MeOH, 10/1) to give(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methoxypyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(42.9 mg, yield: 56%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.77 (1H, m), 2.10-2.18 (2H, m),2.19-2.27 (1H, m), 2.33-2.43 (1H, m), 2.50-2.56 (2H, m), 2.63-2.73 (1H,m), 3.75-3.82 (2H, m), 3.85 (3H, s), 3.88-3.95 (1H, m), 4.04-4.11 (1H,m), 4.56-4.63 (1H, m), 6.49 (1H, s), 7.32-7.48 (3H, m), 8.00-8.04 (1H,m), 8.40-8.44 (1H, m), 8.96 (1H, s), 9.25 (1H, brs).

Example 184:(S)-2-((5-(3,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of N-(4-bromo-2,6-difluorophenyl)-4-chlorobutanamide

To a solution of 4-bromo-2,6-difluoroaniline (5.00 g, 24.0 mmol) andEt₃N (5.0 mL, 36 mmol) in anhydrous THF (50 mL) was added4-chlorobutanoyl chloride (3.5 mL, 31 mmol) dropwise at 0° C. over aperiod of 0.5 hour under N₂ atmosphere. After the addition, theresulting reaction mixture was stirred at 0° C. for 3.5 hours. A yellowsuspension was formed. TLC showed the starting material was consumedcompletely. The reaction mixture was diluted with water (50 mL) and theaqueous layer was extracted with EtOAc (100 mL×2). The combined organiclayer was washed with brine (100 mL), dried over anhydrous Na₂SO₄,filtered and concentrated. The residue was triturated with PE/EtOAc (50mL, 20/1) to give N-(4-bromo-2,6-difluorophenyl)-4-chlorobutanamide (5.7g, yield: 76%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.16-2.25 (2H, m), 2.57-2.70 (2H, m), 3.67(2H, t, J=6.0 Hz), 6.81 (1H, brs), 7.16 (2H, d, J=6.8 Hz).

Step 2: Preparation of 1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one

To a mixture of N-(4-bromo-2,6-difluorophenyl)-4-chlorobutanamide (5.70g, 18.2 mmol) in anhydrous THF (400 mL) was added KOtBu (4.09 g, 36.5mmol) at −10° C. and then the mixture was stirred at 0° C. for 3 hours.A brown suspension was formed. TLC showed the starting material wasconsumed completely. The reaction mixture was poured into sat. aq. NH₄Cl(100 mL) and extracted with EtOAc (200 mL×3). The combined organic layerwas washed with water (100 mL×2), brine (100 mL), dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure. The residuewas triturated with PE/EtOAc (30 mL, 3/1) to give1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one (5.00 g, yield: >99%) asa yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.21-2.31 (2H, m), 2.56 (2H, t, J=8.0 Hz),3.73 (2H, t, J=7.0 Hz), 7.14-7.20 (2H, m).

Step 3: Preparation of1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(4-bromo-2,6-difluorophenyl)pyrrolidin-2-one (500 mg,1.81 mmol), Bispin (552 mg, 2.17 mmol), Pd(dppf)Cl₂ (133 mg, 0.181 mmol)and KOAc (533 mg, 5.43 mmol) in anhydrous dioxane (5 mL) was degassedand purged with N₂ for 3 times. And the resulting mixture was stirred at100° C. for 16 hours under N₂ atmosphere. A black suspension was formed.LCMS showed the purity of the boronic acid of the desired product is 45%(Rt=0.617 min; MS Calcd: 241.1; MS Found: 241.9 [M+H]⁺). The reactionmixture was filtered through a pad of celite, washed with EtOAc (50 mL)and concentrated under reduced pressure to give1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(crude), which was used for the next step without further purification.

Step 4: Preparation of1-(4-(6-chloropyridin-3-yl)-2,6-difluorophenyl)pyrrolidin-2-one

A mixture of1-(2,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(584 mg, 1.81 mmol), 5-bromo-2-chloropyridine (290 mg, 1.51 mmol),Pd(dppf)Cl₂ (110 mg, 0.151 mmol) and Na₂CO₃ (479 mg, 4.52 mmol) indioxane (4 mL) and water (1 mL) was degassed and purged with N₂ for 3times. And the resulting reaction mixture was stirred at 100° C. for 4hours under N₂ atmosphere. A black suspension was formed. LCMS thepurity of the desired product is 34% (Rt=0.896 min; MS Calcd: 308.1; MSFound: 308.9 [M+H]⁺). The reaction mixture was diluted with water (10mL). The aqueous layer was extracted with EtOAc (30 mL×3). The combinedorganic layer was washed with water (20 mL×2), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combi Flash (20% to 60% EtOAc in PE) to give1-(4-(6-chloropyridin-3-yl)-2,6-difluorophenyl)pyrrolidin-2-one (300 mg,yield: 64% for 2 steps) as a light yellow solid ¹H NMR (400 MHz, CDCl₃)δ 2.25-2.35 (2H, m), 2.60 (2H, t, J=8.2 Hz), 3.81 (2H, t, J=7.0 Hz),7.17 (2H, d, J=8.4 Hz), 7.41-7.46 (1H, m), 7.75-7.82 (1H, m), 8.53-8.60(1H, m).

Step 5: Preparation of(S)-2-((5-(3,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloropyridin-3-yl)-2,6-difluorophenyl)pyrrolidin-2-one (50 mg,0.16 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(33 mg, 0.16 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Brettphos (17 mg,0.032 mmol) and Cs₂CO₃ (106 mg, 0.324 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting mixturewas stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS the purity of the desired product is 37%(Rt=0.744 min; MS Calcd: 477.2; MS Found: 478.0 [M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (0.225% FA as an additive) and further triturated with MeCN (3mL) to give(S)-2-((5-(3,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(15.1 mg, yield: 19%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.66-1.77 (1H, m), 2.16-2.27 (3H, m),2.33-2.43 (1H, m), 2.45-2.50 (2H, m), 2.63-2.73 (1H, m), 3.71 (2H, t,J=7.0 Hz), 3.91 (1H, t, J=10.4 Hz), 4.04-4.11 (1H, m), 4.59 (1H, dd,J=10.8 Hz, 2.4 Hz), 6.88 (1H, d, J=8.8 Hz), 7.59 (2H, d, J=9.4 Hz), 7.99(1H, dd, J=8.8 Hz, 2.4 Hz), 8.45 (1H, d, J=2.2 Hz), 8.57 (1H, d, J=2.0Hz), 8.96 (1H, d, J=2.2 Hz), 9.38 (1H, brs).

Example 185:(S)-2-((5-(2,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloropyridin-3-yl)-2,5-difluorophenyl)pyrrolidin-2-one

A mixture of1-(2,5-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(806 mg, 2.49 mmol), 5-bromo-2-chloropyridine (400 mg, 2.08 mmol),Pd(dppf)Cl₂ (152 mg, 0.208 mmol) and Na₂CO₃ (661 mg, 6.24 mmol) indioxane (4 mL) and water (1 mL) was degassed and purged with N₂ for 3times. And the resulting mixture was stirred at 100° C. for 4 hoursunder N₂ atmosphere. A black suspension was formed. LCMS the purity ofthe desired product is 51% (Rt=0.840 min; MS Calcd: 308.1; MS Found:308.9[M+H]⁺). The reaction mixture was diluted with water (10 mL). Theaqueous layer was extracted with EtOAc (30 mL×3). The combined organiclayer was washed with water (20 mL×2), brine (40 mL), dried overanhydrous Na₂SO₄, filtered and concentrated under reduced pressure. Theresidue was purified by Combi Flash (20% to 60% EtOAc in PE) to give1-(4-(6-chloropyridin-3-yl)-2,5-difluorophenyl)pyrrolidin-2-one (600 mg,yield: 94%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.20-2.29 (2H, m), 2.60 (2H, t, J=8.0 Hz),3.90 (2H, t, J=7.0 Hz), 7.16-7.25 (1H, m), 7.37-7.47 (2H, m), 7.81 (1H,d, J=8.2 Hz), 8.53 (1H, s).

Step 2: Preparation of(S)-2-((5-(2,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(6-chloropyridin-3-yl)-2,5-difluorophenyl)pyrrolidin-2-one (50 mg,0.16 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(33 mg, 0.16 mmol), Pd₂(dba)₃ (15 mg, 0.016 mmol), Brettphos (17 mg,0.032 mmol) and Cs₂CO₃ (106 mg, 0.324 mmol) in anhydrous dioxane (3 mL)was degassed and purged with N₂ for 3 times. And the resulting mixturewas stirred at 90° C. for 16 hours under N₂ atmosphere. A yellowsuspension was formed. LCMS the purity of the desired product is 37%(Rt=0.744 min; MS Calcd: 477.2; MS Found: 478.1[M+H]⁺). The reactionmixture was diluted with water (10 mL). The aqueous layer was extractedwith EtOAc (30 mL×3). The combined organic layer was washed with water(20 mL×2), brine (40 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated under reduced pressure. The residue was purified byprep-HPLC (0.225% FA as an additive) and further triturated with MeCN (3mL) to give(S)-2-((5-(2,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(15.1 mg, yield: 19%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.77 (1H, m), 2.08-2.17 (2H, m),2.18-2.27 (1H, m), 2.33-2.43 (1H, m), 2.45-2.50 (2H, m), 2.63-2.73 (1H,m), 3.81 (2H, t, J=6.8 Hz), 3.91 (1H, t, J=10.0 Hz), 4.04-4.11 (1H, m),4.59 (1H, dd, J=10.4 Hz, 2.4 Hz), 6.89 (1H, d, J=8.8 Hz), 7.47-7.60 (2H,m), 7.81 (1H, d, J=8.6 Hz), 8.35 (1H, s), 8.43 (1H, d, J=2.0 Hz), 8.98(1H, d, J=2.2 Hz), 9.36 (1H, brs).

Example 186:(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(965 mg, 3.36 mmol), 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol),K₃PO₄ (1.65 g, 7.75 mmol) and Pd(dppf)Cl₂ (75 mg, 0.10 mmol) were takenup in dioxane (15 mL) and H₂O (3 mL) and the resulting mixture wasstirred at 80° C. for 4 hours. A black solution was formed. LCMS showedthe purity of the desired product is 52% (Rt=0.730 min; MS Calcd: 273.1;MS Found: 273.9 [M+H]⁺). TLC showed the starting material was consumednearly. The mixture was concentrated under reduced pressure. The residuewas purified by Combi Flash (70% EA in PE) to give1-(4-(2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one (500 mg, yield:71%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.18-2.25 (2H, m), 2.66 (2H, t, J=8.0 Hz),3.92 (2H, t, J=7.2 Hz), 7.56 (2H, d, J=8.8 Hz), 7.81 (2H, d, J=9.2 Hz),8.81 (2H, s).

Step 2: Preparation of(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(33 mg, 0.16 mmol), 1-(4-(2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one(40 mg, 0.15 mmol) and con. HCl (43 mg, 42 uL) in EtOH (3 mL) wasstirred at 80° C. for 16 hours. The yellow solution turned tosuspension. LCMS showed that the purity of the desired product is 34%(Rt=0.776 min; MS Calcd: 442.2; MS Found: 443.0 [M+H]⁺). The reactionmixture was filtered and washed with MeCN (10 mL) to give(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(17.4 mg, yield: 27%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.67-1.76 (1H, m), 2.04-2.11 (2H, m),2.20-2.25 (1H, m), 2.35-2.39 (1H, m), 2.54 (2H, overlapped with DMSO),2.62-2.72 (1H, m), 3.85-3.96 (3H, m), 4.02-4.10 (1H, m), 4.59 (1H, dd,J=10.4, 3.2 Hz), 7.70-7.78 (4H, m), 8.29 (1H, d, J=2.4 Hz), 8.80 (2H,s), 9.12 (1H, d, J=2.8 Hz), 9.79 (1H, brs).

Example 187:(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(2-chloropyrimidin-5-yl)-2-fluorophenyl)pyrrolidin-2-one

1-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.02 g, 3.35 mmol), 5-bromo-2-chloropyrimidine (500 mg, 2.58 mmol),K₃PO₄ (1.64 g, 7.74 mmol) and Pd(dppf)Cl₂ (75 mg, 0.10 mmol) were takenup in dioxane (15 mL) and H₂O (3 mL) and the resulting mixture wasstirred at 80° C. for 4 hours. A black solution was formed. LCMS showedthe purity of the desired product is 54% (Rt=0.754 min; MS Calcd: 291.1;MS Found: 291.9 [M+H]⁺). TLC showed the starting material was consumednearly. The mixture was concentrated under reduced pressure. The residuewas purified by Combi Flash (70% EA in PE) to give1-(4-(2-chloropyrimidin-5-yl)-2-fluorophenyl)pyrrolidin-2-one (330 mg,yield: 44%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.20-2.30 (2H, m), 2.61 (2H, t, J=8.0 Hz),3.90 (2H, t, J=7.2 Hz), 7.33-7.39 (2H, m), 7.62-7.67 (1H, m), 8.80 (2H,s).

Step 2: Preparation of(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol),1-(4-(2-chloropyrimidin-5-yl)-2-fluorophenyl)pyrrolidin-2-one (71 mg,0.24 mmol) and con. HCl (72 mg, 73 uL) in EtOH (5 mL) was stirred at 80°C. for 16 hours. The yellow solution turned yellow suspension. LCMSshowed that the purity of the desired product is 77% (Rt=0.602 min; MSCalcd: 460.2; MS Found: 460.9 [M+H]⁺). The reaction mixture was addedEt₃N (1 mL) and concentrated. The residue was diluted with DMF (4 mL)and standing for 2 hours. The mixture was filtered and washed with MeCN(10 mL) to give(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(14.8 mg, yield: 13%) as a yellow solid. The filtrate was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to give(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(8.4 mg, yield: 7%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.76 (1H, m), 2.07-2.17 (2H, m),2.20-2.24 (1H, m), 2.35-2.42 (1H, m), 2.45 (2H, t, J=8.0 Hz), 2.64-2.72(1H, m), 3.78 (2H, t, J=7.2 Hz), 3.91 (1H, t, J=10.4 Hz), 4.03-4.11 (1H,m), 4.59 (1H, dd, J=10.8, 3.2 Hz), 7.52 (1H, t, J=8.4 Hz), 7.60 (1H, dd,J=8.4, 2.0 Hz), 7.72 (1H, dd, J=12.4, 2.0 Hz), 8.28 (1H, d, J=2.4 Hz),8.85 (2H, s), 9.11 (1H, d, J=2.8 Hz), 9.86 (1H, brs).

Example 188:(S)-2-((6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(2-amino-6-chloropyridin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(900 mg, 3.13 mmol), 3-bromo-6-chloropyridin-2-amine (500 mg, 2.41mmol), K₃PO₄ (1.53 g, 7.23 mmol) and Pd(dppf)Cl₂ (70 mg, 0.096 mmol)were taken up in dioxane (15 mL) and H₂O (3 mL). The resulting mixturewas stirred at 80° C. for 4 hours. A black solution was formed. LCMSshowed the purity of the desired product is 48% (Rt=0.715 min; MS Calcd:287.1; MS Found: 287.8 [M+H]⁺). TLC showed the starting material wasremained. The mixture was concentrated under reduced pressure. Theresidue was purified by Combi Flash (90% EA in PE) to give impureproduct (240 mg) as a yellow solid, then triturated with EA:PE=1:1 (10mL) for 1 hour to give1-(4-(2-amino-6-chloropyridin-3-yl)phenyl)pyrrolidin-2-one (121 mg,yield: 17%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.15-2.23 (2H, m), 2.64 (2H, t, J=8.0 Hz),3.91 (2H, t, J=7.2 Hz), 4.58 (2H, brs), 6.48 (2H, d, J=8.0 Hz), 7.42(2H, dd, J=8.8, 2.0 Hz), 7.67 (2H, d, J=8.8 Hz).

Step 2: Preparation of(S)-2-((6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of Pd₂(dba)₃ (22 mg, 0.024 mmol) and Brettphos (26 mg, 0.048mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.243 mmol),1-(4-(2-amino-6-chloropyridin-3-yl)phenyl)pyrrolidin-2-one (77 mg, 0.27mmol) in dioxane (5 mL) and Cs₂CO₃ (198 mg, 0.609 mmol) were added andthe resulting mixture was stirred at 100° C. for 12 hours. A black brownmixture was formed. LCMS showed that1-(4-(2-amino-6-chloropyridin-3-yl)phenyl)pyrrolidin-2-one was consumedcompletely. The reaction mixture was concentrated. The residue waspurified by Combi Flash (8% MeOH in DCM) to give impure product (70 mg)as a yellow gum, then purified by prep-HPLC (0.225% FA as an additive)and lyophilized to give(S)-2-((6-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(2.67 mg, yield: 2%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.61-1.70 (1H, m), 2.01-2.13 (2H, m),2.16-2.25 (1H, m), 2.35-2.40 (1H, m), 2.58-2.63 (3H, m), 3.81-3.88 (3H,m), 3.98-4.03 (1H, m), 4.52-4.57 (1H, m), 5.68 (2H, brs), 6.03 (1H, d,J=7.6 Hz), 7.17 (1H, d, J=8.0 Hz), 7.38 (2H, d, J=8.4 Hz), 7.55 (1H, s),7.68 (2H, d, J=8.4 Hz), 8.17 (1H, s), 8.81 (1H, brs).

Example 189:(S)-2-((6-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridazin-3-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloropyridazin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.25 g, 4.36 mmol), 3,6-dichloropyridazine (500 mg, 3.36 mmol), K₃PO₄(2.14 g, 10.1 mmol) and Pd(dppf)Cl₂ (98 mg, 0.13 mmol) were taken up indioxane (15 mL) and H₂O (3 mL) and the resulting mixture was stirred at80° C. for 4 hours. A black solution was formed. LCMS showed the purityof the desired product is 34% (Rt=0.715 min; MS Calcd: 273.1; MS Found:273.8 [M+H]⁺). TLC showed the starting material was consumed completely.The mixture was concentrated under reduced pressure. The residue waspurified by Combi Flash (EA) to give impure product as a yellow solid,then triturated with CH₃CN (4 mL) for 2 hours to give1-(4-(6-chloropyridazin-3-yl)phenyl)pyrrolidin-2-one (122 mg, yield:13%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.18-2.26 (2H, m), 2.67 (2H, t, J=7.6 Hz),3.94 (2H, t, J=7.2 Hz), 7.55 (1H, d, J=8.8 Hz), 7.80-7.85 (3H, m), 8.08(2H, d, J=8.8 Hz).

Step 2: Preparation of(S)-2-((6-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridazin-3-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(30 mg, 0.15 mmol) and1-(4-(6-chloropyridazin-3-yl)phenyl)pyrrolidin-2-one (40 mg, 0.15 mmol)in EtOH (3 mL) was stirred at 80° C. for 16 hours. A red solution wasformed. LCMS showed the starting material was not consumed. The redsolution was added HCl (43 mg, 44 uL). And the mixture was stirred at80° C. for 16 hours. LCMS showed that the purity of the desired productis 66% (Rt=0.642 min; MS Calcd: 442.2; MS Found: 442.9 [M+H]). Thereaction mixture was filtered and washed with MeCN (10 mL) to give(S)-2-((6-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridazin-3-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(19.0 mg, yield: 29%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.66-1.75 (1H, m), 2.04-2.13 (2H, m),2.21-2.25 (1H, m), 2.37-2.45 (1H, m), 2.57 (2H, overlapped with DMSO),2.67-2.72 (1H, m), 3.87-3.97 (3H, m), 4.05-4.11 (1H, m), 4.63 (1H, dd,J=10.8, 3.2 Hz), 7.41 (1H, d, J=9.6 Hz), 7.84 (2H, d, J=8.8 Hz), 8.04(2H, d, J=8.8 Hz), 8.19 (1H, d, J=9.2 Hz), 8.42 (1H, d, J=2.8 Hz), 8.96(1H, d, J=2.4 Hz), 9.97 (1H, brs).

Example 190:(S)-2-((6-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(904 mg, 3.15 mmol), 3-bromo-6-chloro-2-methylpyridine (500 mg, 2.42mmol), K₃PO₄ (1.54 g, 7.27 mmol) and Pd(dppf)Cl₂ (71 mg, 0.097 mmol)were taken up in dioxane (15 mL) and H₂O (3 mL) and the resultingmixture was stirred at 80° C. for 4 hours. A black solution was formed.LCMS showed the purity of the desired product is 78% (Rt=0.792 min; MSCalcd: 286.1; MS Found: 286.8 [M+H]⁺). TLC showed the starting materialwas consumed completely. The mixture was concentrated under reducedpressure. The residue was purified by Combi Flash (48% EA in PE) to give1-(4-(6-chloro-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (500 mg,yield: 72%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.16-2.25 (2H, m), 2.48 (3H, s), 2.65 (2H, t,J=8.0 Hz), 3.91 (2H, t, J=7.2 Hz), 7.20 (1H, d, J=8.0 Hz), 7.30 (2H, d,J=8.8 Hz), 7.46 (1H, d, J=8.4 Hz), 7.71 (2H, d, J=8.8 Hz).

Step 2: Preparation of(S)-2-((6-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of Pd₂(dba)₃ (22 mg, 0.024 mmol) and Brettphos (26 mg, 0.048mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol),1-(4-(6-chloro-2-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (77 mg, 0.27mmol) in dioxane (5 mL) and Cs₂CO₃ (198 mg, 0.609 mmol) were added andthe resulting mixture was stirred at 100° C. for 14 hours. A black brownmixture was formed. LCMS showed that the purity of the desired productis 57% (Rt=0.667 min; MS Calcd: 455.2; MS Found: 456.0 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give(S)-2-((6-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(24.8 mg, yield: 22%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.63-1.75 (1H, m), 2.04-2.12 (2H, m),2.17-2.25 (1H, m), 2.35-2.42 (4H, m), 2.53 (2H, overlapped with DMSO),2.60-2.73 (1H, m), 3.85-3.91 (3H, m), 4.02-4.10 (1H, m), 4.57 (1H, dd,J=10.8, 2.8 Hz), 6.70 (1H, d, J=8.4 Hz), 7.35 (2H, d, J=8.4 Hz), 7.41(1H, d, J=8.8 Hz), 7.71 (2H, d, J=8.8 Hz), 8.33 (1H, d, J=2.4 Hz), 9.13(1H, brs), 9.31 (1H, d, J=2.4 Hz).

Example 191:(S)-2-((5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloropyridin-3-yl)-3-fluorophenyl)pyrrolidin-2-one

1-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.03 g, 3.38 mmol), 5-bromo-2-chloropyridine (500 mg, 2.60 mmol), K₃PO₄(1.65 g, 7.79 mmol) and Pd(dppf)Cl₂ (76 mg, 0.10 mmol) were taken up indioxane (15 mL) and H₂O (3 mL) and the resulting mixture was stirred at80° C. for 4 hours. A black solution was formed. LCMS showed the purityof the desired product is 40% (Rt=0.784 min; MS Calcd: 290.1; MS Found:290.8 [M+H]⁺). TLC showed the starting material was consumed completely.The mixture was concentrated under reduced pressure. The residue waspurified by Combi Flash (59% EA in PE) to give1-(4-(6-chloropyridin-3-yl)-3-fluorophenyl)pyrrolidin-2-one (240 mg,yield: 32%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.15-2.25 (2H, m), 2.66 (2H, t, J=8.0 Hz),3.89 (2H, t, J=7.6 Hz), 7.38-7.43 (2H, m), 7.46-7.50 (1H, m), 7.69 (1H,d, J=13.6 Hz), 7.83 (1H, d, J=8.8 Hz), 8.55 (1H, s).

Step 2: Preparation of(S)-2-((5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of Pd₂(dba)₃ (22 mg, 0.024 mmol) and Brettphos (26 mg, 0.048mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol),1-(4-(6-chloropyridin-3-yl)-3-fluorophenyl)pyrrolidin-2-one (78 mg, 0.27mmol) in dioxane (5 mL) and Cs₂CO₃ (198 mg, 0.609 mmol) were added andthe resulting mixture was stirred at 100° C. for 14 hours. A black brownmixture was formed. LCMS showed that the purity of the desired productis 53% (Rt=0.673 min; MS Calcd: 459.2; MS Found: 460.0 [M+H]⁺). Thereaction mixture was diluted with DCM (10 mL), filtered andconcentrated. The residue was purified by prep-HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give(S)-2-((5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(24.8 mg, yield: 22%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.72 (1H, m), 2.03-2.11 (2H, m),2.17-2.22 (1H, m), 2.34-2.42 (1H, m), 2.55 (2H, overlapped with DMSO),2.63-2.71 (1H, m), 3.84-3.92 (3H, m), 4.02-4.10 (1H, m), 4.58 (1H, dd,J=10.8, 3.2 Hz), 6.87 (1H, d, J=8.8 Hz), 7.48-7.57 (2H, m), 7.72-7.78(2H, m), 8.30 (1H, s), 8.40 (1H, d, J=2.4 Hz), 8.98 (1H, d, J=2.8 Hz),9.27 (1H, brs).

Example 192:(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one

To a mixture of 4-bromo-3-methylaniline (3.20 g, 17.2 mmol), TEA (1.83g, 18.1 mmol) in THF (50 mL) was added 4-chlorobutanoyl chloride (2.47g, 17.5 mmol) dropwise at 0° C. and stirred for 0.5 hour, the brownsolution was turned into an off-white suspension. TLC (plate 1,PE/EtOAc=5:1) showed the reaction was completed. Then added t-BuOK (4.82g, 43.0 mmol) in portions at 0° C., then warmed to 15° C. and stirredfor another 2.5 hours to give a brown suspension. TLC (plate 2,PE/EtOAc=3/1) showed the reaction was completed. The mixture wasquenched with sat.NH₄Cl (40 mL) and then extracted with EtOAc (30 mL×2).The combined extracts were washed with brine (35 mL×2), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was washed with PE (40 mL) to give1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (4.3 g, yield: 98%) as anoff-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.12 (2H, m), 2.34 (3H, s), 2.48-2.51(2H, m), 3.81 (2H, t, J=6.8 Hz), 7.50 (1H, dd, J=8.8, 2.4 Hz), 7.55 (1H,d, J=8.8 Hz), 7.62 (1H, d, J=2.4 Hz).

Step 2: Preparation of1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

To a mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (2.50 g, 9.84mmol), Bispin (3.75 g, 14.8 mmol), Pd(dppf)Cl₂ (720 mg, 0.984 mmol) indioxane (60 mL) was added KOAc (2.90 g, 29.5 mmol), the resultingmixture was stirred at 90° C. under N₂ atmosphere for 4 hours to give abrown suspension. LCMS showed the purity of the desired product is 78%(Rt=1.837 min; MS Calcd: 301.2; MS Found: 301.9 [M+H]⁺). The mixture wasfiltered. The filtrate was concentrated under reduced pressure to give1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(2.96 g, crude) as a brown solid.

Step 3: Preparation of1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one

To a mixture of1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(689 mg, 2.29 mmol), 5-bromo-2-chloro-pyridine (400 mg, 2.08 mmol),Pd(dppf)Cl₂ (152 mg, 0.208 mmol) in dioxane (12 mL) was added Na₂CO₃(441 mg, 4.16 mmol) and H₂O (2 mL), the resulting mixture was stirred at90° C. under N₂ atmosphere for 4 hours to give a brown suspension. LCMSshowed the purity of the desired product is 37% (Rt=0.821 min; MS Calcd:286.1; MS Found: 286.9 [M+H]⁺). The mixture was diluted with water (30mL) and extracted with EtOAc (35 mL×2). The combined extracts werewashed with brine (35 mL×2), dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by Combi Flash (PE/EtOAc=6/1 to 3/1 to 3/2) to give1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one (300 mg,yield: 41%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.12 (2H, m), 2.26 (3H, s), 2.48-2.51(2H, m), 3.87 (2H, t, J=6.8 Hz), 7.28 (1H, d, J=8.0 Hz), 7.58-7.65 (3H,m), 7.89 (1H, dd, J=8.0, 2.4 Hz), 8.41 (1H, d, J=2.4 Hz).

Step 4: Preparation of(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

To a mixture of1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one (60 mg, 0.21mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(39 mg, 0.19 mmol) in dioxane (5 mL) was added Brettphos (10 mg, 0.019mmol), Cs₂CO₃ (124 mg, 0.38 mmol) and Pd₂(dba)₃ (17 mg, 0.019 mmol), theresulting mixture was purged with N₂ for 3 times and stirred at 50° C.for 0.5 hour, then heated to 95° C. for 15.5 hours under N₂ atmosphereto give a brown solution. LCMS showed the purity of desired product is20% (Rt=1.296 min; MS Calcd: 492.2; MS Found: 456.1 [M+H]⁺). The mixturewas filtered. The filter cake was washed with DCM (10 mL×2). Thefiltrate was concentrated under reduced pressure to give a residue. Theresidue was purified by Combi Flash (DCM/MeOH=100/1 to 10/1), thenfurther purified by prep-HPLC (0.225% FA as an additive) purification togive(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(11.5 mg, yield: 13%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.74 (1H, m), 2.02-2.12 (2H, m),2.18-2.25 (1H, m), 2.28 (3H, s), 2.34-2.44 (1H, m), 2.48-2.51 (2H, m),2.61-2.72 (1H, m), 3.85 (2H, t, J=6.8 Hz), 3.86-3.92 (1H, m), 4.04-4.10(1H, m), 4.57-4.61 (1H, m), 6.89 (1H, d, J=8.4 Hz), 7.22 (1H, d, J=8.8Hz), 7.51-7.59 (2H, m), 7.64 (1H, dd, J=8.4, 0.8 Hz), 8.06 (1H, s), 8.42(1H, s), 8.93 (1H, s), 9.34 (1H, brs).

Example 193:(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of (5-bromo-2-chloropyridin-4-yl)methanol

To a mixture of 5-bromo-2-chloroisonicotinaldehyde (1.00 g, 4.54 mmol)in THF (15 mL) was added NaBH₄ (172 mg, 4.54 mmol) in portions at 0° C.,then warmed to 20° C. and stirred for 2 hours to give a yellowsuspension. TLC (PE/EtOAc=3/1) showed the reaction was completed. Themixture was quenched with water (15 mL), then adjusted to pH=3-4 withHCl (1 M). The mixture was extracted with EtOAc (30 mL×2). The combinedextracts were washed with brine (30 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by Combi Flash (PE/EtOAc=8/1 to 6/1 to 5/1) to give(5-bromo-2-chloropyridin-4-yl)methanol (820 mg, yield: 81%) as a whitesolid.

¹H NMR (400 MHz, DMSO-d₆) δ 4.52 (2H, s), 5.80 (1H, brs), 7.54 (1H, s),8.52 (1H, s).

Step 2: Preparation of 5-bromo-2-chloro-4-(methoxymethyl)pyridine

To a mixture of (5-bromo-2-chloropyridin-4-yl)methanol (350 mg, 1.57mmol) in anhydrous THF (10 mL) was added NaH (94 mg, 2.4 mmol, 60%purity dispersed in mineral oil) in portions at 0° C. and stirred for0.5 hour, the colorless solution turn to a brown solution, then addedMeI (456 mg, 3.21 mmol) dropwise at 0° C., then warmed to 25° C. andstirred for 2.5 hours to give a pale yellow solution. TLC (PE/EtOAc=5/1)showed the reaction was completely. The mixture was quenched with icewater (10 mL), then extracted with EtOAc (20 mL×2), the combinedextracts were washed with brine (25 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by Combi Flash (PE/EtOAc=10/1 to 8/1) to give5-bromo-2-chloro-4-(methoxymethyl)pyridine (260 mg, yield: 70%) as acolorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ 3.43 (3H, s), 4.47 (2H, s), 7.49 (1H, s),8.57 (1H, s).

Step 3: Preparation of1-(4-(6-chloro-4-(methoxymethyl)pyridin-3-yl)phenyl)pyrrolidin-2-one

To a mixture of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(300 mg, 1.04 mmol), 5-bromo-2-chloro-4-(methoxymethyl)pyridine (247 mg,1.04 mmol), Pd(dppf)Cl₂ (76 mg, 0.10 mmol) in dioxane (10 mL) was addedNa₂CO₃ (277 mg, 2.61 mmol) and H₂O (2 mL), the resulting mixture wasstirred at 95° C. under N₂ atmosphere for 3 hours to give a brownsuspension. LCMS showed the purity of desired product is 81% (Rt=0.835min; MS Calcd: 316.1; MS Found: 317.1 [M+H]⁺). The mixture was filtered.The filter cake was washed with EtOAc (10 mL). The filtrate was dilutedwith water (20 mL), then extracted with EtOAc (30 mL×2). The combinedextracts were washed with brine (30 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by Combi Flash (PE/EtOAc=3/1 to 1/1 to 1/2) (TLC:PE/EtOAc=1/1) to give1-(4-(6-chloro-4-(methoxymethyl)pyridin-3-yl)phenyl)pyrrolidin-2-one(300 mg, yield: 91%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.12 (2H, m), 2.48-2.51 (2H, m), 3.31(3H, s), 3.89 (2H, t, J=6.8 Hz), 4.41 (2H, s), 7.44 (2H, d, J=8.8 Hz),7.56 (1H, s), 7.79 (2H, d, J=8.8 Hz), 8.30 (1H, s).

Step 4: Preparation of(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

To a mixture of1-(4-(6-chloro-4-(methoxymethyl)pyridin-3-yl)phenyl)pyrrolidin-2-one (85mg, 0.27 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol), Pd₂(dba)₃ (22 mg, 0.024 mmol), Brettphos (13 mg,0.024 mmol) in dioxane (6 mL) was added Cs₂CO₃ (159 mg, 0.487 mmol), theresulting mixture was stirred at 50° C. under N₂ atmosphere for 1 hour.Then heated to 95° C. and stirred for another 3 hours under N₂atmosphere to give a brown suspension. LCMS showed the purity of desiredproduct is 33% (Rt=0.742 min; MS Calcd: 485.2; MS Found: 486.2 [M+H]⁺).The mixture was filtered. The filter cake was washed with DCM (10 mL×2).The filtrate was concentrated under reduced pressure to give a residue.The residue was purified by Combi Flash (DCM/MeOH=100/1 to 10/1) (TLC:DCM/MeOH=15/1), then further purified by prep-HPLC (0.225% FA as anadditive) to give(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(15.0 mg, yield: 12%) as a pale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.65-1.74 (1H, m), 2.02-2.12 (2H, m),2.15-2.22 (1H, m), 2.31-2.42 (1H, m), 2.48-2.51 (2H, m), 2.65-2.72 (1H,m), 3.31 (3H, s), 3.82-3.90 (3H, m), 4.00-4.10 (1H, m), 4.35 (2H, s),4.55-4.61 (1H, m), 6.99 (1H, s), 7.36 (2H, d, J=8.8 Hz), 7.73 (2H, d,J=8.8 Hz), 7.95 (1H, s), 8.36 (1H, d, J=2.4 Hz), 8.95 (1H, d, J=2.4 Hz),9.35 (1H, brs).

Example 194:(S)-2-((3-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(6-chloro-5-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

To a mixture of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(890 mg, 3.10 mmol), 5-bromo-2-chloro-3-methylpyridine (400 mg, 1.94mmol), Pd(dppf)Cl₂ (85 mg, 0.12 mmol) in dioxane (12 mL) was addedNa₂CO₃ (616 mg, 5.81 mmol) and H₂O (2 mL), the resulting mixture wasstirred at 80° C. under N₂ atmosphere for 5 hours to give a brownsuspension. LCMS showed the purity of desired product is 73% (Rt=1.642min; MS Calcd: 286.1; MS Found: 286.8 [M+H]⁺). The mixture was dilutedwith water (30 mL) and extracted with EtOAc (35 mL×2). The combinedextracts were washed with brine (35 mL×2), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas washed with EtOAc/PE (5 mL/30 mL) to give1-(4-(6-chloro-5-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (450 mg,yield: 81%) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.02-2.12 (2H, m), 2.41 (3H, s), 2.48-2.51(2H, m), 3.89 (2H, t, J=6.8 Hz), 7.72-7.85 (4H, m), 8.15 (1H, d, J=2.0Hz), 7.79 (1H, d, J=2.0 Hz).

Step 2: Preparation of(S)-2-((3-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

To a mixture of1-(4-(6-chloro-5-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (60 mg, 0.21mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(39 mg, 0.19 mmol) in dioxane (5 mL) was added Brettphos (10 mg, 0.019mmol), Cs₂CO₃ (124 mg, 0.380 mmol) and Pd₂(dba)₃ (17 mg, 0.019 mmol),the resulting mixture was purged with N₂ for 3 times and stirred at 50°C. for 0.5 hour, then heated to 95° C. for 15.5 hours under N₂atmosphere to give a brown solution. LCMS showed the purity of desiredproduct is 13% (Rt=1.288 min; MS Calcd: 455.2; MS Found: 456.0 [M+H]⁺).The mixture was filtered. The filter cake was washed with DCM (10 mL×2).The filtrate was concentrated under reduced pressure to give a residue.The residue was purified by Combi Flash (DCM/MeOH=100:1 to 10:1), thenfurther purified by prep-HPLC (0.225% FA as an additive) purification togive(S)-2-((3-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(7.7 mg, yield: 9%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.74 (1H, m), 2.04-2.11 (2H, m),2.16-2.27 (1H, m), 2.35 (3H, s), 2.38-2.46 (1H, m), 2.49-2.52 (2H, m),2.66-2.71 (1H, m), 3.86 (2H, t, J=7.2 Hz), 3.89-3.96 (1H, m), 4.02-4.14(1H, m), 4.52-4.64 (1H, m), 7.66 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.8Hz), 7.87 (1H, s), 8.16-8.25 (2H, m), 8.31-8.47 (1H, m), 8.96 (1H, brs).

Example 195:(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(4-bromophenyl)pyrrolidin-2-one (16.0 g, 66.6 mmol),Bispin (20.3 g, 80.0 mmol) and KOAc (14.0 g, 199 mmol) and Pd(dppf)Cl₂(1.46 g, 2.00 mmol) in dioxane (300 mL) was stirred at 100° C. for 17hours. The yellow solution turned to suspension. LCMS showed the purityof product is 63% (Rt=0.713 min; MS Calcd: 287.2; MS Found: 288.2[M+H]⁺). The reaction mixture was cooled to 20° C. and filtered throughsilica gel then washed with PE/EA (1/1, 2 L). The solvent was evaporatedunder reduced pressure to give1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(33.0 g, crude) as a yellow gum.

Step 2: Preparation of1-(4-(2-chloro-4-methoxypyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.41 g, 4.92 mmol), 5-bromo-2-chloro-4-methoxypyrimidine (1.00 g, 4.48mmol), K₃PO₄ (2.85 g, 13.4 mmol) and Pd(dppf)Cl₂ (140 mg, 0.179 mmol)were taken up in dioxane (25 mL) and H₂O (5 mL), the mixture was stirredat 80° C. for 4 hours. A black solution was formed. LCMS showed thepurity of product is 23% (Rt=0.670 min; MS Calcd: 303.1; MS Found: 303.9[M+H]⁺). The reaction mixture was diluted EtOAc (10 mL) and extractedwith EtOAc (10 mL×2). The mixture was concentrated under reducedpressure. The residue was purified by Combi Flash (50% to 80% EtOAc inPE) to give1-(4-(2-chloro-4-methoxypyrimidin-5-yl)phenyl)pyrrolidin-2-one (500 mg,yield: 37% for two steps) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.15-2.25 (2H, m), 2.65 (2H, t, J=8.0 Hz),3.91 (2H, t, J=7.2 Hz), 4.06 (3H, s), 7.55-7.65 (2H, m), 7.69-7.77 (2H,m), 8.34 (1H, s).

Step 3: Preparation of(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(2-chloro-4-methoxypyrimidin-5-yl)phenyl)pyrrolidin-2-one (60 mg,0.19 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(40 mg, 0.19 mmol) and con. HCl (15 uL) in DMF (3 mL) was stirred at 80°C. for 16 hours. The yellow solution turned to suspension. LCMS showedthat 1-(4-(2-chloro-4-methoxypyrimidin-5-yl)phenyl)pyrrolidin-2-one wasremained. Then the(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(40 mg, 0.19 mmol) was added to the suspension, and stirred at 80° C.for 12 hours. LCMS-2 showed the purity of product is 50% (Rt=1.386 min;MS Calcd: 472.2; MS Found: 473.0 [M+H]⁺). The reaction mixture wasfiltered and the solid was washed with CH₃CN (3 mL). The filtrate waspurified by HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to givea solid. The solid was triturated with CH₃CN (2 mL) to give(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(7.0 mg, yield: 7%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.59-1.75 (1H, m), 2.01-2.13 (2H, m),2.16-2.26 (1H, m), 2.36-2.43 (1H, m), 2.54 (2H, overlapped with DMSO),2.65-2.71 (1H, m), 3.84-3.95 (3H, m), 3.98-4.03 (3H, m), 4.04-4.11 (1H,m), 4.57 (1H, dd, J=10.8, 3.2 Hz), 7.55 (2H, d, J=8.8 Hz), 7.69 (2H, d,J=7.2 Hz), 8.17 (1H, d, J=2.4 Hz), 8.30 (1H, s), 9.34 (1H, s), 9.75 (1H,s).

Example 196:(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(2-chloro-4-methylpyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(2.08 g, 7.23 mmol), 5-bromo-2-chloro-4-methylpyrimidine (1.00 g, 4.82mmol), K₃PO₄ (3.07 g, 14.5 mmol) and Pd(dppf)Cl₂ (141 mg, 0.193 mmol)were taken up in dioxane (25 mL) and H₂O (5 mL). The resulting mixturewas stirred at 80° C. for 4 hours. A black solution was formed. LCMSshowed the purity of product is 21% (Rt=0.688 min; MS Calcd: 287.1; MSFound: 288.0 [M+H]⁺). The reaction mixture was diluted with EtOAc (10mL) and extracted with EtOAc (10 mL×2). The mixture was concentratedunder reduced pressure. The residue was purified by Combi Flash (10% to35% EtOAc in PE) to give1-(4-(2-chloro-4-methylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (320 mg,yield: 23%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.20-2.24 (2H, m), 2.52 (3H, s), 2.66 (2H, t,J=8.0 Hz), 3.92 (2H, t, J=6.8 Hz), 7.29-7.34 (2H, m), 7.74-7.77 (2H, m),8.40 (1H, s).

Step 2: Preparation of(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(2-chloro-4-methylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (77 mg,0.26 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol) and con. HCl (56 uL) in DMF (4 mL) was stirred at 80°C. for 16 hours. The yellow solution turned to suspension. LCMS showedthat the 1-(4-(2-chloro-4-methylpyrimidin-5-yl)phenyl)pyrrolidin-2-onewas remained. Then added(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(15 mg, 0.24 mmol) was stirred at 80° C. for 12 hours. The yellowsolution turned to suspension. LCMS showed the purity of product is 23%(Rt=0.798 min; MS Calcd: 456.2; MS Found: 457.1 [M+H]⁺). The reactionmixture was filtered to give a yellow solid. The yellow solid waspurified by HPLC (0.225% FA as additive) and lyophilized to give(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(12 mg, yield: 11%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.69-1.80 (1H, m), 2.19-2.25 (2H, m),2.30-2.40 (1H, m), 2.45 (3H, s), 2.55-2.63 (1H, m), 2.64-2.69 (2H, m),2.70-2.79 (1H, m), 3.86-3.95 (3H, m), 4.08-4.17 (1H, m), 4.63 (1H, dd,J=10.8, 3.2 Hz), 7.08 (1H, s), 7.31 (2H, d, J=8.4 Hz), 7.71 (2H, d,J=8.8 Hz), 8.23-8.28 (2H, m), 9.33 (1H, d, J=2.4 Hz).

Example 197:(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of methyl5-chloro-2-(methylthio)pyrimidine-4-carboxylate

Oxalyl chloride (15.5 g, 122 mmol) was added dropwise to a mixture of5-chloro-2-(methylthio)pyrimidine-4-carboxylic acid (5.0 g, 24 mmol) inDCM (80 mL) and DMF (357 mg, 4.89 mmol) at 0° C. The mixture was stirredat 15° C. for 2 h. The mixture was concentrated. MeOH (50 mL) was addeddropwise to the residue at 0° C. and stirred at 15° C. for 2 h to give abrown solution. TLC showed the starting material was consumed. Themixture was concentrated. The residue was purified by flash silica gelchromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of09% Ethyl acetate/Petroleum ether gradient @40 mL/min) to give methyl5-chloro-2-(methylthio)pyrimidine-4-carboxylate (5.2 g, yield: 98%) as awhite solid.

¹H NMR (400 MHz, CDCl₃) δ 2.58 (3H, s), 4.00 (3H, s), 8.60 (1H, s).

Step 2: Preparation of (5-chloro-2-(methylthio)pyrimidin-4-yl)methanol

DIBAL-H (1 M in toluene, 48 mL, 48 mmol) in toluene was added dropwiseto a solution of methyl 5-chloro-2-(methylthio)pyrimidine-4-carboxylate(5.2 g, 24 mmol) in DCM (100 mL) at −60° C. The mixture was slowlywarmed to 15° C., and stirred at 15° C. for 15 h to give a yellowsolution. LCMS showed that the purity of the desired product is 64%(Rt=0.648 min; MS Calcd: 190.0; MS Found: 190.8 [M+H]⁺). TLC showed onemain spot with larger polarity was detected. The mixture was quenchedwith sat.aq.NH₄Cl (150 mL), diluted with EtOAc (150 mL) and filtered.The mixture was extracted with EtOAc (150 mL×2). The combined organiclayer was dried over anhydrous Na₂SO₄, filtered and concentrated underreduced pressure. The residue was purified by flash silica gelchromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of08% Ethyl acetate/Petroleum ether gradient @40 mL/min) to give(5-chloro-2-(methylthio)pyrimidin-4-yl)methanol (1.8 g, yield: 40%) as apale yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 2.54 (3H, s), 4.58 (2H, d, J=6.4 Hz), 5.46(1H, t, J=6.4 Hz), 8.66 (1H, s).

Step 3: Preparation of5-chloro-4-(methoxymethyl)-2-(methylthio)pyrimidine

Me₃₀BF₄ (698 mg, 4.72 mmol) was added to a mixture of(5-chloro-2-(methylthio)pyrimidin-4-yl)methanol (900 mg, 4.72 mmol) andN1,N1,N8,N8-tetramethylnaphthalene-1,8-diamine (1.5 g, 7.1 mmol) in DCM(20 mL). The mixture was stirred at 20° C. for 1 h to give a brownsuspension. LCMS showed that the purity of the desired product is 44%(Rt=0.739 min; MS Calcd: 204.0; MS Found: 204.8 [M+H]⁺). TLC showed onespot with lower polarity was detected. The mixture was diluted with MeOH(10 mL) and concentrated. The residue was purified by flash silica gelchromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of05% Ethyl acetate/Petroleum ether gradient @30 mL/min) to give5-chloro-4-(methoxymethyl)-2-(methylthio)pyrimidine (650 mg, crude) asyellow oil.

¹H NMR (400 MHz, DMSO-d₆) δ 2.53 (3H, s), 3.37 (3H, s), 4.54 (2H, s),8.71 (1H, s).

Step 4: Preparation of1-(4-(4-(methoxymethyl)-2-(methylthio)pyrimidin-5-yl)phenyl)pyrrolidin-2-one

A mixture of 5-chloro-4-(methoxymethyl)-2-(methylthio)pyrimidine (100mg, 0.489 Mmol),1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(309 mg, 1.07 mmol), Cs₂CO₃ (318 mg, 0.977 mmol) and Pd(t-Bu₃P)₂ (12 mg,0.024 mmol) in dioxane (2 mL) and H₂O (0.4 mL) was stirred at 100° C.for 5 h under N₂ to give a black suspension. LCMS showed that the purityof the desired product is 35% (Rt=1.542 min; MS Calcd: 329.1; MS Found:330.1 [M+H]⁺). TLC showed one main spot with larger polarity wasdetected. The mixture was combined with ES9451-41 and filtered andconcentrated. The residue was purified by flash silica gelchromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of050% Ethyl acetate/Petroleum ether gradient @ 35 mL/min) to give1-(4-(4-(methoxymethyl)-2-(methylthio)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(49% for two steps) as colorless oil.

¹H NMR (400 MHz, DMSO-d₆) δ 1.07 (3H, s), 2.02-2.14 (2H, m), 2.53 (2H,t, J=8.0 Hz), 3.26 (3H, s), 3.88 (2H, t, J=6.8 Hz), 4.38 (2H, s), 7.48(2H, d, J=8.8 Hz), 7.78 (2H, d, J=8.8 Hz), 8.59 (1H, s).

Step 5: Preparation of1-(4-(4-(methoxymethyl)-2-(methylsulfonyl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one

The mixture of1-(4-(4-(methoxymethyl)-2-(methylthio)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(380 mg, 1.15 mmol) and m-CPBA (468 mg, 2.31 mmol, 85% purity) in DCM(20 mL) was stirred at 20° C. for 30 min to give a pale yellowsuspension. LCMS showed that the purity of the desired product is 65%(Rt=1.335 min; MS Calcd: 361.1; MS Found: 362.0 [M+H]⁺). TLC showed thestarting material was consumed. The mixture was diluted with DCM (50 mL)and quenched with sat.aq.Na₂SO₃ (50 mL). The mixture was washed withsat.aq.NaHCO₃ (50 mL×2). The organic layer was dried over anhydrousNa₂SO₄, filtered and concentrated under reduced pressure to give1-(4-(4-(methoxymethyl)-2-(methylsulfonyl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(370 mg, crude) as a yellow solid.

Step 6: Preparation of(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

TFA (32 mg, 0.28 mmol) was added to a solution of1-(4-(4-(methoxymethyl)-2-(methylsulfonyl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(50 mg, 0.14 mmol) and2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(57 mg, 0.28 mmol) in THF (1.5 mL). The mixture was stirred at 70° C.for 15 h under N₂ to give a brown solution. LCMS showed the desired MSwas detected and most of1-(4-(4-(methoxymethyl)-2-(methylsulfonyl)pyrimidin-5-yl)phenyl)pyrrolidin-2-onewere remained. The mixture was stirred at 70° C. for 20 h under N₂ togive brown solution. LCMS showed that the purity of the desired productis 49% (Rt=1.403 min; MS Calcd: 486.2; MS Found: 487.2 [M+H]⁺). Themixture was concentrated. The residue was purified by prep-HPLC (0.225%FA as an additive) and lyophilized to give(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(13.6 mg, yield: 18% for two steps) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.77 (1H, m), 2.03-2.14 (2H, m),2.17-2.26 (1H, m), 2.34-2.43 (1H, m), 2.52 (2H, t, J=8.0 Hz), 2.64-2.74(1H, m), 3.28 (3H, s), 3.82-3.97 (3H, m), 4.00-4.14 (1H, m), 4.35 (2H,s), 4.58 (1H, dd, J=10.8, 2.8 Hz), 7.46 (2H, d, J=8.4 Hz), 7.75 (2H, d,J=8.4 Hz), 8.30 (1H, d, J=2.4 Hz), 8.40 (1H, s), 9.25 (1H, d, J=2.4 Hz),9.85 (1H, s).

Example 198:(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one

A mixture of 1-(4-bromo-3-methylphenyl)pyrrolidin-2-one (2.90 g, 11.4mmol), Bispin (3.48 g, 13.7 mmol) and K(OAc) (2.40 g, 34.2 mmol) andPd(dppf)Cl₂ (250 mg, 0.342 mmol) in dioxane (60 mL) was stirred at 100°C. for 17 hours. The yellow solution turned to suspension. LCMS showedthe purity of product is 67% (Rt=0.950 min; MS Calcd: 301.2; MS Found:301.9 [M+H]⁺). The reaction mixture was cooled to 20° C. and filteredthrough silica gel then washed with PE/EA (1/1, 300 mL). The solvent wasevaporated under reduced pressure to give1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(5.00 g, crude) as a yellow gum.

Step 2: Preparation of1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one

1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.71 g, 5.69 mmol), 5-bromo-2-chloropyrimidine (1.00 g, 5.17 mmol),K₃PO₄ (3.29 g, 15.5 mmol), Pd(dppf)Cl₂ (151 mg, 0.207 mmol) were takenup in dioxane (25 mL) and H₂O (5 mL). The resulting mixture was stirredat 80° C. for 4 hours. A black solution was formed. LCMS showed thepurity of product is 46% (Rt=0.644 min; MS Calcd: 287.2; MS Found: 287.9[M+H]⁺). The reaction mixture was diluted with EtOAc (10 mL) andextracted with EtOAc (10 mL×2). The mixture was concentrated underreduced pressure. The residue was purified by Combi Flash (20% to 50%EtOAc in PE), to give1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one (686 mg,yield: 46% for two steps) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.16-2.26 (2H, m), 2.33 (3H, s), 2.66 (2H, t,J=8.0 Hz), 3.91 (2H, t, J=7.2 Hz), 7.21 (1H, d, J=8.4 Hz), 7.55-7.59(1H, dd, J=8.4, 2.4 Hz), 7.65 (1H, d, J=2.4 Hz), 8.61 (2H, s).

Step 3: Preparation of(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one (60 mg,0.21 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(42 mg, 0.21 mmol) and con. HCl (16 uL) in DMF (3 mL) was stirred at 80°C. for 16 hours. A yellow solution was formed. LCMS showed that1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one wasremained. Then added(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(20 mg, 0.10 mmol) and con. HCl (16 uL) in yellow solution was stirredat 80° C. for 6 hours. LCMS showed that1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one wasremained. The yellow solution was added(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(60 mg, 0.30 mmol) and con. HCl (16 uL), stirred at 80° C. for 12 hours.LCMS showed the purity of product is 20% (Rt=0.611 min; MS Calcd: 456.2;MS Found: 457.2 [M+H]⁺). The yellow solution was purified by HPLC(0.225% FA as an additive) and lyophilized to give(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(20 mg, yield: 20%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.63-1.73 (1H, m), 2.02-2.11 (2H, m),2.14-2.23 (1H, m), 2.31 (3H, s), 2.34-2.43 (1H, m), 2.53 (2H, overlappedwith DMSO), 2.64-2.69 (1H, m), 3.84-3.94 (3H, m), 4.03-4.11 (1H, m),4.59 (1H, dd, J=10.4, 2.8 Hz), 7.28 (1H, d, J=9.2 Hz) 7.57-7.62 (2H, m),8.29 (1H, d, J=2.4 Hz), 8.47 (2H, s), 9.10 (1H, d, J=2.8 Hz), 9.74 (1H,s).

Example 199:(S)-2-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of1-(4-(4-amino-2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(227 mg, 0.792 mmol), 5-bromo-2-chloro-6-methylpyrimidin-4-amine (150mg, 0.719 mmol), K₃PO₄ (458 mg, 2.16 mmol) and Pd(dppf)Cl₂ (21 mg, 0.029mmol) were taken up in dioxane (8 mL) and H₂O (2 mL), the resultingmixture was stirred at 80° C. for 4 hours. A black solution was formed.LCMS showed the purity of product is 52% (Rt=0.561 min; MS Calcd: 288.1;MS Found: 288.9 [M+H]⁺). The reaction mixture was diluted with EtOAc (10mL), and extracted with EtOAc (10 mL×2). The mixture was concentratedunder reduced pressure. The residue was purified by Combi Flash (60% to100% EtOAc in PE) to give1-(4-(4-amino-2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one (150 mg,yield: 72%) as a white solid.

¹H NMR (400 MHz, CDCl₃) δ 2.17-2.26 (2H, m), 2.66 (2H, t, J=8.0 Hz),3.91 (2H, t, J=7.2 Hz), 5.29 (2H, brs), 7.38-7.42 (2H, m), 7.74-7.78(2H, m), 8.00 (1H, s).

Step 2: Preparation of(S)-2-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of1-(4-(4-amino-2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one (50.0 mg,0.173 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(35.5 mg, 0.173 mmol) and con. HCl (40 uL) in DMF (3 mL) was stirred at80° C. for 16 hours. The yellow solution turned to suspension. LCMSshowed the purity of product is 75% (Rt=0.527 min; MS Calcd: 457.2; MSFound: 458.2 [M+H]⁺). The reaction mixture was filtered to give a yellowsolid. The yellow solid was purified by HPLC (0.225% FA as additive) andlyophilized to give(S)-2-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(27.8 mg, yield: 35%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.63-1.75 (1H, m), 2.04-2.13 (2H, m),2.17-2.25 (1H, m), 2.33-2.42 (1H, m), 2.53 (2H, overlapped with DMSO),2.61-2.71 (1H, m), 3.80-3.92 (3H, m), 4.01-4.09 (1H, m), 4.58 (1H, dd,J=10.8, 3.2 Hz), 6.69 (2H, brs), 7.40 (2H, d, J=3.6 Hz), 7.69-7.84 (3H,m), 8.39 (1H, d, J=2.4 Hz), 8.96 (1H, d, J=2.4 Hz), 9.32 (1H, brs).

Example 200:(S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(2-chloro-4-methoxypyrimidin-5-yl)phenyl)pyrrolidin-2-one (57.8 mg,0.190 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol) and con. HCl (39 uL) in DMF (3 mL) was stirred at 80°C. for 16 hours. The yellow solution was formed. LCMS showed the purityof product is 35% (Rt=0.634 min; MS Calcd: 498.2; MS Found: 499.1[M+H]⁺). The yellow solution was purified by HPLC (0.05% NH₃.H₂O as anadditive) and lyophilized to give(S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(10.6 mg, yield: 12%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.80-0.83 (1H, m), 0.89-0.93 (1H, m),0.96-1.04 (1H, m), 1.05-1.11 (1H, m), 1.96-2.04 (1H, m), 1.99-2.11 (2H,m), 2.14-2.21 (1H, m), 2.49 (2H, overlapped with DMSO), 3.85 (2H, t,J=6.8 Hz), 3.97-4.03 (4H, m), 4.17-4.20 (1H, m), 4.61 (1H, dd, J=10.8,3.2 Hz), 7.53 (2H, d, J=8.8 Hz), 7.68 (2H, d, J=8.8 Hz), 8.16 (1H, d,J=2.8 Hz), 8.28 (1H, s), 9.23 (1H, d, J=2.8 Hz), 9.71 (1H, s).

Example 201:(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(2-chloro-4-methylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (55 mg,0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol) and con. HCl (39 uL) in DMF (3 mL) was stirred at 80°C. for 16 hours. A yellow solution was formed. LCMS showed the purity ofproduct is 69% (Rt=0.644 min; MS Calcd: 482.2; MS Found: 483.2 [M+H]⁺).The yellow solution was purified by HPLC (0.05% NH₃.H₂O as an additive)and lyophilized to give(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(7.2 mg, yield: 8.6%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.80-0.86 (1H, m), 0.91-1.03 (2H, m),1.06-1.13 (1H, m), 1.96-2.02 (1H, m), 2.05-2.11 (2H, m), 2.15-2.20 (1H,m), 2.37 (3H, s), 2.51 (2H, overlapped with DMSO), 3.87 (2H, t, J=6.8Hz), 3.96-4.02 (1H, m), 4.17-4.21 (1H, m), 4.60 (1H, dd, J=10.8, 3.2Hz), 7.41 (2H, d, J=8.8 Hz), 7.74 (2H, d, J=8.4 Hz), 8.22 (1H, d, J=2.8Hz), 8.25 (1H, s), 9.25 (1H, d, J=2.4 Hz), 9.70 (1H, s).

Example 202:(S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

The mixture of1-(4-(4-(methoxymethyl)-2-(methylsulfonyl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(80 mg, 0.22 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(80 mg, 0.35 mmol) and TFA (38 mg, 0.33 mmol) in THF (2 mL) was stirredat 70° C. under N₂ for 55 h to give a brown solution. LCMS showed thatthe purity of the desired product is 49% (Rt=1.500 min; MS Calcd: 512.2;MS Found: 513.3 [M+H]⁺). The mixture was concentrated. The residue waspurified by prep-HPLC (0.225% FA as an additive) and lyophilized. Theresidue was purified by prep-HPLC (normal phase: [10% DCM in PE-EtOH]),concentrated and lyophilized to give(S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(2.8 mg, yield: 2.2% for two steps) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.82-0.89 (1H, m), 0.92-0.98 (1H, m),0.98-1.04 (1H, m), 1.07-1.13 (1H, m), 1.96-2.04 (1H, m), 2.06-2.13 (2H,m), 2.17-2.24 (1H, m), 2.52-2.56 (2H, m), 3.28 (3H, s), 3.88 (2H, t,J=6.8 Hz), 3.96-4.06 (1H, m), 4.14-4.26 (1H, m), 4.35 (2H, s), 4.61 (1H,dd, J=10.8, 3.6 Hz), 7.45 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.8 Hz),8.30 (1H, d, J=2.4 Hz), 8.40 (1H, s), 9.18 (1H, d, J=2.4 Hz), 9.84 (1H,s).

Example 203:(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(2-chloropyrimidin-5-yl)-3-methylphenyl)pyrrolidin-2-one (27 mg,0.094 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(24 mg, 0.10 mmol), Pd₂(dba)₃ (9 mg, 0.009 mmol), Brettphos (10 mg,0.019 mmol) and Cs₂CO₃ (92 mg, 0.28 mmol) in dioxane (3 mL) was stirredat 100° C. for 17 hours under N₂. A black suspension was formed. LCMSshowed the purity of product is 14% (Rt=0.599 min; MS Calcd: 481.0; MSFound: 482.2 [M+H]⁺). The reaction mixture combined with batch(6012-738) was concentrated. The residue was purified by Combi Flash (5%DCM in MeOH) to give impure product. The product was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to give(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(9.1 mg, yield: 7%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.84-0.87 (1H, m), 0.93-0.97 (1H, m),0.98-1.06 (1H, m), 1.07-1.11 (1H, m), 1.96-2.00 (1H, m), 2.02-2.10 (2H,m), 2.15-2.22 (1H, m), 2.30 (3H, s), 2.56 (2H, overlapped with DMSO),3.86 (2H, t, J=7.2 Hz), 4.00 (1H, t, J=10.4 Hz), 4.18-4.22 (1H, m), 4.62(1H, dd, J=10.8, 3.2 Hz), 7.27 (1H, d, J=8.8 Hz), 7.56-7.62 (2H, m),8.25 (1H, d, J=2.8 Hz), 8.46 (2H, s), 9.08 (1H, d, J=2.8 Hz), 9.75 (1H,s).

Example 204:(S)-2′-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(4-amino-2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one (49 mg,0.17 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol) and con. HCl (13 uL) in DMF (3 mL) was stirred at 80°C. for 16 hours. The yellow solution turned to suspension. LCMS showedthe purity of product is 85% (Rt=0.568 min; MS Calcd: 483.2; MS Found:484.2 [M+H]⁺). The reaction mixture was filtered. The filtrate wasconcentrated to was purified by HPLC (0.05% NH₃.H₂O as an additive) andlyophilized to give(S)-2′-((4-amino-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(15.8 mg, yield: 18%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.82-0.87 (1H, m), 0.93-1.04 (2H, m),1.06-1.13 (1H, m), 1.97-2.02 (1H, m), 2.07-2.11 (2H, m), 2.17-2.22 (1H,m), 2.52 (2H, overlapped with DMSO), 3.87 (2H, t, J=2.8 Hz), 3.95-4.01(1H, m), 4.14-4.23 (1H, m), 4.60 (1H, dd, J=7.6, 3.2 Hz), 6.28 (2H,brs), 7.40 (2H, d, J=8.8 Hz), 7.73 (2H, d, J=8.4 Hz), 7.80 (1H, s), 8.39(1H, d, J=2.4 Hz), 9.00 (1H, d, J=2.4 Hz), 9.10 (1H, s).

Example 205:(S)-2′-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of 1-(4-(2-chloropyrimidin-5-yl)phenyl)pyrrolidin-2-one (52mg, 0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol) and con.HCl (39 uL) in EtOH (3 mL) was stirred at 80°C. for 16 hours. The yellow solution turned to suspension. LCMS showedthe purity of product is 56% (Rt=0.620 min; MS Calcd: 468.2; MS Found:469.2 [M+H]⁺). The reaction mixture was filtered and washed with CH₃CN(2 mL). The filtrate was purified by HPLC (0.225% FA as additive) andlyophilized to give(S)-2′-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(2.76 mg, yield: 3%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.85-1.11 (4H, m), 1.97-2.07 (1H, m),2.05-2.13 (2H, m), 2.16-2.23 (1H, m), 2.52 (2H, overlapped with DMSO),3.87 (2H, t, J=7.2 Hz), 3.98-4.03 (1H, m), 4.16-4.25 (1H, m), 4.62 (1H,dd, J=11.2, 3.2 Hz), 7.68-7.79 (4H, m), 8.24 (1H, d, J=2.8 Hz), 8.80(2H, s), 9.12 (1H, d, J=2.4 Hz), 9.79 (1H, s).

Example 206:(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

Step 1: Preparation of1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(2.08 g, 7.23 mmol), 5-bromo-2-chloro-4-methylpyridine (995 mg, 4.82mmol), K₃PO₄ (3.07 g, 14.5 mmol) and Pd(dppf)Cl₂ (141 mg, 0.193 mmol)were taken up in dioxane (25 mL) and H₂O (5 mL). The resulting mixturewas stirred at 80° C. for 4 hours. A black solution was formed. LCMSshowed the purity of product is 57% (Rt=0.688 min; MS Calcd: 286.1; MSFound: 286.9 [M+H]⁺). The reaction mixture was diluted with EtOAc (10mL), and extracted with EtOAc (10 mL×2). The mixture was concentratedunder reduced pressure. The residue was purified by Combi Flash (10% to40% EtOAc in PE) to give1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (700 mg,yield: 51%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.17-2.24 (2H, m), 2.28 (3H, s), 2.65 (2H, t,J=8.0 Hz), 3.91 (2H, t, J=7.2 Hz), 7.24 (1H, s), 7.27-7.32 (2H, m),7.70-7.74 (2H, m), 8.19 (1H, s).

Step 2: Preparation of(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of Pd₂(dba)₃ (8 mg, 0.008 mmol) and Xantphos (10 mg, 0.017mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(20 mg, 0.086 mmol),1-(4-(6-chloro-4-methylpyridin-3-yl)phenyl)pyrrolidin-2-one (30 mg, 0.10mol) in dioxane (4 mL) and Cs₂CO₃ (70 mg, 0.22 mmol) were added. Theresulting mixture was stirred at 100° C. for 12 hours. A black brownmixture was formed. LCMS showed that the purity of the desired productis 5% (Rt=0.615 min; MS Calcd: 481.2; MS Found: 482.3 [M+H]⁺). Thereaction mixture was work-up together with other batches (es6012-722,es6012-723). The mixture was added H₂O (5 mL) dropwise. The formedprecipitate was filtered off and washed sequentially with MeOH (10 mL)and dried to give the product as a grey solid. The solid was suspendedin MeOH (10 mL) at 15° C. Aq. HCl (1M, 10 mL) was added to give a blacksolution. Active charcoal (100 mg) was added and the mixture was stirredat 15° C. for 30 min. The mixture was filtered through celite and thecelite rinsed with MeOH (10 mL). The filtrate pH adjusted to 7-8 usingaq. NaOH (2 M, 3 mL). After 30 min, the precipitate was filtered off,washed sequentially with MeOH (10 mL) to give a yellow solid (100 mg).The residue was triturated with MeCN (5 mL) for 10 hours to give(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(90.3 mg, yield: 73%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.84-0.87 (1H, m), 0.93-0.97 (1H, m),1.00-1.08 (1H, m), 1.09-1.13 (1H, m), 2.02-2.10 (3H, m), 2.16-2.22 (1H,m), 2.28 (3H, s), 2.56 (2H, overlapped with DMSO), 3.85 (2H, t, J=7.2Hz), 4.08 (1H, t, J=10.4 Hz), 4.20-4.26 (1H, m), 4.73 (1H, dd, J=10.8,3.2 Hz), 7.07 (1H, s), 7.37 (2H, d, J=8.8 Hz), 7.75 (2H, d, J=8.4 Hz),7.80 (1H, s), 8.04 (1H, d, J=2.4 Hz), 8.65 (1H, d, J=2.4 Hz), 10.4 (1H,brs).

Example 207:(S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(6-chloro-4-(methoxymethyl)pyridin-3-yl)phenyl)pyrrolidin-2-one (60mg, 0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol), Pd₂(dba)₃ (15 mg, 0.017 mmol), Brettphos (18 mg,0.034 mmol) and Cs₂CO₃ (141 mg, 0.432 mmol) in dioxane (3 mL) wasstirred at 100 C for 17 hours under N₂. A black suspension was formed.LCMS showed the(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-onewas remained. Then the mixture was added Pd₂(dba)₃ (10 mg, 0.017 mmol),Brettphos (15 mg, 0.034 mmol), Cs₂CO₃ (100 mg, 0.432 mmol) and dioxane(2 mL) was stirred at 100° C. for 12 hours under N₂. A black suspensionwas formed. LCMS showed the purity of product is 22% (Rt=0.608 min; MSCalcd: 511.2; MS Found: 512.1 [M+H]⁺). The reaction mixture was dilutedwith DCM (10 mL), filtered and concentrated. The residue was purified byHPLC (0.225% FA as additive) and lyophilized, the solid was dissolvedwith DMF purified by prep-HPLC (0.05% NH₃.H₂O as an additive) andlyophilized to give(S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(9.6 mg, yield: 11%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.80-1.08 (4H, m), 1.96-2.02 (1H, m),2.05-2.10 (2H, m), 2.15-2.21 (1H, m), 2.52 (2H, overlapped with DMSO),3.30 (3H, s), 3.87 (2H, t, J=7.2 Hz), 3.98 (1H, t, J=10.0 Hz), 4.16-4.21(1H, m), 4.33 (2H, s), 4.59 (1H, dd, J=11.2, 2.4 Hz), 6.95 (1H, s), 7.35(2H, d, J=8.4 Hz), 7.71 (2H, d, J=8.8 Hz), 7.95 (1H, s), 8.32 (1H, d,J=2.4 Hz), 8.97 (1H, d, J=2.4 Hz), 9.21 (1H, s).

Example 208:(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

Step 1: Preparation of1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one

1-(3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(1.72 g, 5.72 mmol), 5-bromo-2-chloropyridine (1.00 g, 5.20 mmol), K₃PO₄(3.31 g, 15.6 mmol) and Pd(dppf)Cl₂ (152 mg, 0.208 mmol) were taken upin dioxane (25 mL) and H₂O (5 mL). The resulting mixture was stirred at80° C. for 4 hours. A black solution was formed. LCMS showed the purityof product is 47% (Rt=0.686 min; MS Calcd: 286.2; MS Found: 286.9[M+H]⁺). The reaction mixture was diluted with EtOAc (10 mL), andextracted with EtOAc (10 mL×2). The mixture was concentrated underreduced pressure. The residue was purified by Combi Flash (10% to 40%EtOAc in PE) to give1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one (520 mg,yield: 35%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 2.15-2.24 (2H, m), 2.29 (3H, s), 2.64 (2H, t,J=7.6 Hz), 3.90 (2H, t, J=7.2 Hz), 7.20 (1H, d, J=8.4 Hz), 7.36-7.41(1H, m), 7.20 (1H, dd, J=8.4 Hz, 2.4 Hz), 7.58-7.62 (2H, m), 8.35 (1H,d, J=1.6 Hz).

Step 2: Preparation of(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of 1-(4-(6-chloropyridin-3-yl)-3-methylphenyl)pyrrolidin-2-one(59 mg, 0.21 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol), Pd₂(dba)₃ (15 mg, 0.017 mmol), Brettphos (18 mg,0.034 mmol) and Cs₂CO₃ (141 mg, 0.432 mmol) in dioxane (5 mL) wasstirred at 100° C. for 17 hours under N₂. A black suspension was formed.LCMS showed the purity of product is 44% (Rt=0.599 min; MS Calcd: 481.2;MS Found: 482.2 [M+H]⁺). The reaction mixture was diluted with DCM (10mL), filtered and concentrated. The residue was purified by prep-HPLC(0.225% FA as additive) and lyophilized to give(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(9.7 mg, yield: 12%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.80-0.87 (1H, m), 0.93-0.97 (1H, m),0.98-1.05 (1H, m), 1.07-1.13 (1H, m), 1.96-2.11 (3H, m), 2.15-2.23 (1H,m), 2.27 (3H, s), 2.48 (2H, overlapped with DMSO), 3.85 (2H, t, J=8.8Hz), 3.99 (1H, t, J=7.2 Hz), 4.15-4.27 (1H, m), 4.60 (1H, dd, J=11.2,2.8 Hz), 6.84 (1H, d, J=8.4 Hz), 7.21 (1H, d, J=9.2 Hz), 7.52-7.62 (3H,m), 8.07 (1H, d, J=2.8 Hz), 8.37 (1H, d, J=2.4 Hz), 8.94 (1H, d, J=2.4Hz), 9.18 (1H, s).

Example 209:(3S,6R)—N,N-dimethyl-6-(6-(((S)-9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxamide

Step 1: Preparation of 1-(6-chloropyridin-3-yl)but-3-en-1-ol

To a solution of 6-chloronicotinaldehyde (2.50 g, 17.7 mmol) inanhydrous THF (25 mL) was added allylmagnesium bromide (21.2 mL, 21.2mmol, 1M in Et₂O) dropwise at 0° C. After the addition, the reactionmixture was stirred at 0° C. for 2 hours. The reaction mixture turnedinto red suspension from yellow solution. The reaction mixture wasquenched with NH₄Cl (50 mL, saturated aqueous) and extracted with EtOAc(50 mL×3). The combined organic layer was washed with brine (50 mL),dried over anhydrous Na₂SO₄ and concentrated. The residue was purifiedby Combi Flash (20% to 35% EtOAc in PE) to give1-(6-chloropyridin-3-yl)but-3-en-1-ol (2.45 g, yield: 76%) as blue gum.

¹H NMR (400 MHz, CDCl₃) δ 2.21 (1H, brs), 2.42-2.60 (2H, m), 4.80 (1H,dd, J=8.0, 4.8 Hz), 5.15-5.25 (2H, m), 5.73-5.85 (1H, m), 7.32 (1H, d,J=8.4 Hz), 7.69 (1H, dd, J=8.0, 2.4 Hz), 8.36 (1H, d, J=2.8 Hz).

Step 2: Preparation of ethyl2-(((1-(6-chloropyridin-3-yl)but-3-en-1-yl)oxy)methyl)acrylate

To a solution of 1-(6-chloropyridin-3-yl)but-3-en-1-ol (2.45 g, 13.3mmol) in anhydrous THF (60 mL) was added NaH (1.60 g, 40.0 mmol, 60%dispersion in mineral oil) portion-wise at 0° C. Then the reactionmixture was stirred at 10-15° C. for 1 hour. The reaction mixture turnedinto red suspension from yellow. The mixture was cooled to 0° C. andethyl 2-(bromomethyl)acrylate (5.15 g, 26.7 mmol) was added dropwise at0° C. The reaction mixture was stirred at 10-15° C. for another 1 hour.The reaction mixture turned into yellow suspension from red. Thereaction mixture was quenched with saturated aqueous NH₄Cl (50 mL), thenextracted with EtOAc (100 mL×2). The combined organic layer was washedwith brine (50 mL), dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by Combi Flash (10% to 20% EtOAc in PE) to giveethyl 2-(((1-(6-chloropyridin-3-yl)but-3-en-1-yl)oxy)methyl)acrylate(2.70 g, yield: 68%) as colorless gum.

¹H NMR (400 MHz, CDCl₃) δ 1.29 (3H, t, J=7.2 Hz), 2.38-2.47 (1H, m),2.56-2.65 (1H, m), 4.00-4.12 (2H, m), 4.20 (2H, q, J=7.2 Hz), 4.42 (1H,t, J=6.8 Hz), 4.99-5.08 (2H, m), 5.67-5.80 (1H, m), 5.88-5.91 (1H, m),6.29-6.31 (1H, m), 7.33 (1H, d, J=8.0 Hz), 7.63 (1H, dd, J=8.4, 2.4 Hz),8.30 (1H, d, J=2.4 Hz).

Step 3: Preparation of ethyl6-(6-chloropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate

1^(st) Batch

A mixture of ethyl2-(((1-(6-chloropyridin-3-yl)but-3-en-1-yl)oxy)methyl)acrylate (800 mg,2.70 mmol) and Grubbs (II) catalyst (84 mg, 0.14 mmol) in anhydrous DCM(150 mL) was degassed and purged with N₂ for 3 times. Then the resultingreaction mixture was stirred at 40° C. for 16 hours under N₂ atmosphere.The reaction mixture turned into dark green solution from yellow. Thereaction mixture was concentrated and the residue was purified by CombiFlash (5% to 15% EtOAc in PE) to give ethyl6-(6-chloropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate (410 mg,yield: 57%) as green gum.

¹H NMR (400 MHz, CDCl₃) δ 1.31 (3H, t, J=7.2 Hz), 2.42-2.50 (2H, m),4.24 (2H, q, J=7.2 Hz), 4.42-4.50 (1H, m), 4.54 (1H, dd, J=10.0, 4.0Hz), 4.61-4.68 (1H, m), 7.07-7.12 (1H, m), 7.34 (1H, d, J=8.4 Hz), 7.70(1H, dd, J=8.4, 2.4 Hz), 8.38 (1H, d, J=2.4 Hz).

2^(nd) Batch

A mixture of ethyl2-(((1-(6-chloropyridin-3-yl)but-3-en-1-yl)oxy)methyl)acrylate (1.90 g,6.42 mmol) and Grubbs (II) catalyst (201 mg, 0.321 mmol) in anhydrousDCM (350 mL) was degassed and purged with N₂ for 3 times. Then theresulting reaction mixture was stirred at 40° C. for 16 hours under N₂atmosphere. The reaction mixture turned into dark green solution fromyellow. The reaction mixture was concentrated and the residue waspurified by Combi Flash (5% to 15% EtOAc in PE) to give ethyl6-(6-chloropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate (1.40 g,yield: 81%) as green gum.

Step 4: Preparation of ethyl(3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate

A solution of ethyl6-(6-chloropyridin-3-yl)-5,6-dihydro-2H-pyran-3-carboxylate (1.10 g,4.11 mmol) and PtO₂ (93 mg, 0.41 mmol) in EtOAc (20 mL) was stirredunder H₂ 15 psi at 20° C. for 5 hours. The yellow solution turned toblack. LCMS showed the purity of the desired product was 74% (Rt=0.724min; MS Calcd: 269.1; MS Found: 269.9 [M+H]⁺). TLC indicated one majornew spot with larger polarity was detected. The mixture was filtered andthe filtrate was concentrated. The residue was purified by Combi Flash(20% EA in PE) to give ethyl(3S,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate (800mg, yield: 72%) as a colorless gum and ethyl(3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate (245mg, yield: 22%) as a yellow gum.

Step 5: Preparation of(3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylic acid

ethyl (3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylate(150 mg, 0.556 mmol) was dissolved in THF (5 mL) and H₂O (5 mL) andtreated with LiOH—H₂O (70 mg, 1.7 mmol) at 15° C. for 12 hours. Theyellow solution turned to black. Crude LCMS showed that the purity ofproduct was 80% (Rt=0.652 min, MS Calcd.: 241.0; MS Found: 241.9[M+H]⁺). THF was removed under reduced pressure. The aqueous layer waswashed with EtOAc (10 mL). The combined organic layers were washed withNaHCO₃ (5 mL×2, saturated aqueous). The organic extract was added to theoriginal aqueous layers. The pH was the adjusted to 4 with HCl (3 M).The precipitate was filtered, washed with water and dried in vacuo togive (3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylicacid (92 mg, yield: 68%) as an off-white solid. Used for the next stepwithout further purification.

¹H NMR (400 MHz, DMSO-d₆) δ 1.44-1.50 (1H, m), 1.68-1.75 (1H, m),1.88-1.94 (1H, m), 2.08-2.13 (1H, m), 2.54 (1H, overlapped with DMSO),3.52 (1H, t, J=11.6 Hz), 4.13-4.20 (1H, m), 4.37-4.44 (1H, m), 7.49 (1H,d, J=8.4 Hz), 7.80 (1H, dd, J=8.4, 2.4 Hz), 8.37 (1H, d, J=2.0 Hz),12.45 (1H, brs).

Step 6: Preparation of(3R,6S)-6-(6-chloropyridin-3-yl)-N,N-dimethyltetrahydro-2H-pyran-3-carboxamide

To a mixture of(3R,6S)-6-(6-chloropyridin-3-yl)tetrahydro-2H-pyran-3-carboxylic acid(92 mg, 0.38 mmol) in DMF (5 mL) was added EDCI (145 mg, 0.761 mmol),HOBt (103 mg, 0.761 mmol), TEA (115 mg, 1.14 mmol) and Me₂NH.HCl (62 mg,0.76 mmol), the reaction mixture was stirred at 50° C. for 2 hours togive a grey suspension. LCMS showed the purity of the desired product is34% (Rt=0.651 min; MS Calcd: 268.1; MS Found: 268.9 [M+H]⁺). TLCindicated one major new spot with lower polarity was detected. Thereaction mixture was concentrated. The residue was purified by CombiFlash (68% EA in PE) to give(3R,6S)-6-(6-chloropyridin-3-yl)-N,N-dimethyltetrahydro-2H-pyran-3-carboxamide(100 mg, yield: 98%) as a yellow gum.

Step 7: Preparation of(3S,6R)—N,N-dimethyl-6-(6-(((S)-9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxamide

A mixture of Pd₂(dba)₃ (17 mg, 0.018 mmol) and Brettphos (20 mg, 0.037mmol) in 1,4-dioxane (1 mL) was stirred at 50° C. for 10 min.(3R,6S)-6-(6-chloropyridin-3-yl)-N,N-dimethyltetrahydro-2H-pyran-3-carboxamide(100 mg, 0.372 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(76 mg, 0.37 mmol) in dioxane (7 mL) and Cs₂CO₃ (266 mg, 0.818 mmol)were added and the resulting mixture was stirred at 100° C. for 15hours. A black brown mixture was formed. LCMS showed that the purity ofthe desired product is 19% (Rt=0.596 min; MS Calcd: 437.2; MS Found:438.1 [M+H]⁺). The reaction mixture was diluted with DCM (10 mL),filtered and concentrated. The residue was purified by prep-HPLC (0.05%NH₃.H₂O as an additive) and lyophilized to give(3S,6R)—N,N-dimethyl-6-(6-(((S)-9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxamide(15.0 mg, yield: 9%) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 1.62-1.75 (4H, m), 1.76-1.95 (1H, m),2.18-2.23 (1H, m), 2.33-2.40 (1H, m), 2.60-2.68 (1H, m), 2.80 (3H, s),2.85-2.93 (1H, m), 3.05 (3H, s), 3.52 (1H, t, J=11.2 Hz), 3.88 (1H, t,J=10.4 Hz), 3.96-3.99 (1H, m), 4.02-4.08 (1H, m), 4.28 (1H, d, J=11.2Hz), 4.56 (1H, dd, J=10.8, 3.2 Hz), 6.75 (1H, d, J=8.4 Hz), 7.52 (1H,dd, J=8.4, 2.0 Hz), 8.06 (1H, d, J=2.0 Hz), 8.33-8.36 (1H, m), 8.93-8.95(1H, m), 9.07 (1H, brs).

Example 210:(S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(6-chloro-4-isopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (60 mg,0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol) Brettphos (19 mg,0.035 mmol) and Cs₂CO₃ (141 mg, 0.432 mmol) in dioxane (3 mL) wasstirred at 100° C. for 16 hours under N₂. A black suspension was formed.LCMS showed that the purity of the desired product is 45% (Rt=0.588 min;MS Calcd: 497.2; MS Found: 498.0 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL) filtered and concentrated. The residue waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized. 1HNMR-1 indicated the product is impure. It was further purified byprep-TLC (DCM/MeOH, 10/1) and lyophilized. 1H NMR-2 indicated theproduct is impure. The residue was purified by prep-HPLC (0.05% NH₃.H₂Oas an additive) and lyophilized to give(S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(3.11 mg, yield: 4%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.82-0.87 (1H, m), 0.87-0.95 (1H, m),0.95-1.02 (1H, m), 1.02-1.07 (1H, m), 1.09 (6H, d, J=6.8 Hz), 1.95-2.01(1H, m), 2.01-2.13 (2H, m), 2.13-2.21 (1H, m), 2.53 (2H, overlapped withDMSO), 2.93-3.02 (1H, m), 3.88 (2H, t, J=7.2 Hz), 3.98 (1H, t, J=10.4Hz), 4.17-4.26 (1H, m), 4.56-4.64 (1H, m), 6.79 (1H, s), 7.29 (1H, s),7.31 (1H, s), 7.71 (1H, s), 7.73 (1H, s), 7.86 (1H, s), 8.31 (1H, d,J=2.4 Hz), 8.94 (1H, d, J=2.4 Hz), 9.11 (1H, s).

Example 211:(S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(6-chloro-4-cyclopropylpyridin-3-yl)phenyl)pyrrolidin-2-one (54 mg,0.17 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol), Brettphos (19 mg,0.035 mmol) and Cs₂CO₃ (141 mg, 0.432 mmol) in dioxane (3 mL) wasstirred at 100° C. for 16 hours under N₂. A black suspension was formed.LCMS showed that the purity of the desired product is 28% (Rt=0.628 min;MS Calcd: 507.2; MS Found: 508.0 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL), filtered and concentrated. The residue waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized togive(S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(5.5 mg, yield: 6%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.68-0.77 (2H, m), 0.81-0.86 (1H, m),0.92-1.04 (4H, m), 1.06-1.14 (1H, m), 1.76-1.84 (1H, m), 1.95-2.03 (1H,m), 2.04-2.14 (2H, m), 2.14-2.21 (1H, m), 2.52 (2H, overlapped withDMSO), 3.87 (2H, t, J=6.8 Hz), 3.94-4.02 (1H, m), 4.14-4.21 (1H, m),4.59 (1H, dd, J=10.8, 3.2 Hz), 6.33 (1H, s), 7.43 (2H, d, J=8.8 Hz),7.73 (2H, d, J=8.4 Hz), 7.90 (1H, s), 8.29 (1H, d, J=2.4 Hz), 8.92 (1H,d, J=2.8 Hz), 9.02 (1H, s).

Example 212:(S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(6-chloro-4-methoxypyridin-3-yl)phenyl)pyrrolidin-2-one (58 mg,0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol), Pd₂(dba)₃ (16 mg, 0.017 mmol), Brettphos (19 mg,0.035 mmol) and Cs₂CO₃ (141 mg, 0.432 mmol) in dioxane (3 mL) wasstirred at 100° C. for 16 hours under N₂. A black suspension was formed.LCMS showed that the purity of the desired product is 25% (Rt=0.588 min;MS Calcd: 497.2; MS Found: 498.0 [M+H]⁺). The reaction mixture wasdiluted with DCM (10 mL) filtered and concentrated. The residue waspurified by prep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized togive(S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(3.38 mg, yield: 4%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.82-0.87 (1H, m), 0.91-0.97 (1H, m),0.96-1.04 (1H, m), 1.07-1.13 (1H, m), 1.96-2.04 (1H, m), 2.04-2.10 (2H,m), 2.15-2.12 (1H, m), 2.52 (2H, overlapped with DMSO), 3.80 (3H, s),3.86 (2H, t, J=7.6 Hz), 3.99 (1H, t, J=10.4 Hz), 4.17-4.23 (1H, m), 4.60(1H, dd, J=10.8, 2.8 Hz), 6.45 (1H, s), 7.46 (2H, d, J=8.4 Hz), 7.66(2H, d, J=8.8 Hz), 7.94 (1H, s), 8.32 (1H, d, J=2.4 Hz), 8.95 (1H, d,J=2.4 Hz), 9.15 (1H, s).

Example 213:(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 5-bromo-2-chloro-4-cyclopropylpyrimidine

A solution of 5-bromo-2,4-dichloropyrimidine (3.00 g, 13.2 mmol),cyclopropylboronic acid (1.13 g, 13.2 mmol), K₂CO₃ (5.45 g, 39.4 mmol)and Pd(PPh₃)₄ (500 mg, 0.432 mmol) in DMF (6 mL) and toluene (30 mL) wasstirred at 120° C. for 15 hours. A black mixture was formed. LCMS showedthe purity of the desired product was 43% (Rt=0.810 min; MS Calcd:234.0; MS Found: 234.6 [M+H]⁺). TLC showed the starting material wasconsumed completely. The mixture was filtered and the filtrate wasconcentrated. The residue was purified by Combi Flash (9% EA in PE) togive 5-bromo-2-chloro-4-cyclopropylpyrimidine (635 mg, yield: 21%) ascolorless oil.

¹H NMR (400 MHz, CDCl₃) δ 1.20-1.25 (2H, m), 1.27-1.33 (2H, m),2.42-2.48 (1H, m), 8.49 (1H, s).

Step 2: Preparation of1-(4-(2-chloro-4-cyclopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(750 mg, 2.61 mmol), 5-bromo-2-chloro-4-cyclopropylpyrimidine (628 mg,2.69 mmol), K₃PO₄ (1.66 g, 7.84 mmol) and Pd(dppf)Cl₂ (76 mg, 0.10 mmol)were taken up in dioxane (15 mL) and H₂O (3 mL) and the resultingmixture was stirred at 80° C. for 4 hours. A black solution was formed.LCMS showed the purity of the desired product is 70% (Rt=0.805 min; MSCalcd: 313.1; MS Found: 313.9 [M+H]⁺). The mixture was concentratedunder reduced pressure. The residue was purified by Combi Flash (68% EAin PE) to give1-(4-(2-chloro-4-cyclopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (580mg, yield: 71%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.03-1.08 (2H, m), 1.30-1.34 (2H, m),2.05-2.12 (1H, m), 2.19-2.25 (2H, m), 2.66 (2H, t, J=8.0 Hz), 3.92 (2H,t, J=7.2 Hz), 7.43 (2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 8.30 (1H,s).

Step 3: Preparation of(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

A mixture of(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(50 mg, 0.24 mmol),1-(4-(2-chloro-4-cyclopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (76mg, 0.24 mmol) in DMF (4 mL) was added con. HCl (70 uL). And the mixturewas stirred at 80° C. for 30 hours. A red solution was formed. LCMSshowed that the purity of the desired product is 20% (Rt=0.734 min; MSCalcd: 482.2; MS Found: 483.0 [M+H]⁺). The solution was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to give(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(11.5 mg, yield: 10%) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.94-0.98 (2H, m), 1.16-1.22 (2H, m),1.68-1.73 (1H, m), 1.98-2.02 (1H, m), 2.05-2.12 (2H, m), 2.18-2.24 (1H,m), 2.35-2.43 (1H, m), 2.53 (2H, t, J=6.4 Hz), 2.62-2.70 (1H, m),3.83-3.93 (3H, m), 4.02-4.08 (1H, m), 4.58 (1H, dd, J=6.8, 2.4 Hz), 7.46(2H, d, J=8.8 Hz), 7.76 (2H, d, J=8.8 Hz), 8.18-8.20 (2H, m), 9.08 (1H,d, J=2.0 Hz), 9.54 (1H, brs).

Example 214:(S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

A mixture of1-(4-(2-chloro-4-cyclopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (54mg, 0.17 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(40 mg, 0.17 mmol) in DMF (4 mL) was added con.HCl (50 uL). And themixture was stirred at 80° C. for 30 hours. A red solution was formed.LCMS showed that the purity of the desired product is 13% (Rt=0.775 min;MS Calcd: 508.2; MS Found: 509.1 [M+H]⁺). The solution was purified byprep-HPLC (0.05% NH₃.H₂O as an additive) and lyophilized to give(S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(5.5 mg, yield: 6%) as a yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 0.84-0.87 (1H, m), 0.90-0.96 (3H, m),1.00-1.03 (1H, m), 1.06-1.10 (1H, m), 1.42-1.81 (2H, m), 1.96-2.02 (2H,m), 2.04-2.12 (2H, m), 2.15-2.22 (1H, m), 2.53 (2H, overlapped withDMSO), 3.87 (2H, t, J=7.2 Hz), 3.99 (1H, t, J=10.4 Hz), 4.16-4.21 (1H,m), 4.61 (1H, dd, J=7.2, 2.8 Hz), 7.45 (2H, d, J=8.8 Hz), 7.76 (2H, d,J=8.8 Hz), 8.18-8.20 (2H, m), 9.01 (1H, d, J=2.4 Hz), 9.53 (1H, brs).

Example 215:(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

Step 1: Preparation of 5-bromo-2-chloro-4-(prop-1-en-2-yl)pyrimidine

5-bromo-2,4-dichloropyrimidine (1.16 g, 5.09 mmol), potassiumtrifluoro(prop-1-en-2-yl)borate (753 mg, 5.09 mmol), K₃PO₄ (3.24 g, 15.2mmol) and Pd(dppf)Cl₂ (148 mg, 0.203 mmol) were taken up in dioxane (20mL) and H₂O (4 mL) and the resulting mixture was stirred at 80° C. for14 hours. A black solution was formed. LCMS showed the purity of thedesired product is 51% (Rt=0.819 min; MS Calcd: 231.9; MS Found: 232.7[M+H]⁺). The mixture was concentrated under reduced pressure. Theresidue was purified by Combi Flash (3% EA in PE) to give5-bromo-2-chloro-4-(prop-1-en-2-yl)pyrimidine (535 mg, yield: 45%) aslight yellow oil.

¹H NMR (400 MHz, CDCl₃) δ 2.17 (3H, s), 5.60 (2H, d, J=15.6 Hz), 8.69(1H, s).

Step 2: Preparation of1-(4-(2-chloro-4-(prop-1-en-2-yl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one

1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-2-one(600 mg, 2.09 mmol), 5-bromo-2-chloro-4-(prop-1-en-2-yl)pyrimidine (526mg, 2.26 mmol), K₃PO₄ (1.33 g, 6.27 mmol) and Pd(dppf)Cl₂ (61 mg, 0.083mmol) were taken up in dioxane (15 mL) and H₂O (3 mL) and the resultingmixture was stirred at 80° C. for 14 hours. A black solution was formed.LCMS showed the purity of the desired product is 85% (Rt=0.802 min; MSCalcd: 313.1; MS Found: 313.8 [M+H]⁺). The mixture was concentratedunder reduced pressure. The residue was purified by Combi Flash (48% EAin PE) to give1-(4-(2-chloro-4-(prop-1-en-2-yl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(340 mg, yield: 52%) as a yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.94 (3H, s), 2.18-2.24 (2H, m), 2.65 (2H, t,J=7.6 Hz), 3.90 (2H, t, J=7.2 Hz), 5.34 (2H, d, J=15.6 Hz), 7.34 (2H, t,J=8.8 Hz), 7.73 (2H, d, J=8.4 Hz), 8.48 (1H, s).

Step 3: Preparation of1-(4-(2-chloro-4-isopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one

A solution of1-(4-(2-chloro-4-(prop-1-en-2-yl)pyrimidin-5-yl)phenyl)pyrrolidin-2-one(280 mg, 0.892 mmol) and PtO₂ (20 mg, 0.089 mmol) in EtOAc (15 mL) wasstirred under H₂ 15 psi at 20° C. for 14 hours. The yellow solutionturned to black. LCMS showed the purity of the desired product was 67%(Rt=0.825 min; MS Calcd: 315.1; MS Found: 315.8 [M+H]⁺). TLC indicatedpolarity of the starting material was same as the product. The mixturewas filtered and the filtrate was concentrated. The residue was purifiedby Combi Flash (50% EA in PE) to give1-(4-(2-chloro-4-isopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (221mg, yield: 78%) as a light yellow solid.

¹H NMR (400 MHz, CDCl₃) δ 1.22 (6H, d, J=6.8 Hz), 2.18-2.25 (2H, m),2.66 (2H, t, J=8.0 Hz), 3.15-3.22 (1H, m), 3.92 (2H, t, J=6.8 Hz), 7.28(2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.8 Hz), 8.37 (1H, s).

Step 4: Preparation of(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

To a mixture of1-(4-(2-chloro-4-isopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (60 mg,0.19 mmol),(S)-2-amino-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(78 mg, 0.38 mmol) in DMF (4 mL) was added con.HCl (50 uL). The reactionmixture was stirred at 80° C. for 48 hours to give a brown solution.LCMS showed the purity of product is 12% (Rt=0.641 min; MS Calcd: 484.2;MS Found: 485.2 [M+H]⁺). The mixture was directly purified by prep-HPLC(0.225% FA as an additive) purification to give(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one(18.3 mg, yield: 20%) as an off-white solid.

1H NMR (400 MHz, DMSO-d₆) δ 1.18 (3H, d, J=6.8 Hz), 1.22 (3H, d, J=6.8Hz), 1.64-1.75 (1H, m), 2.05-2.14 (2H, m), 2.16-2.26 (1H, m), 2.35-2.44(1H, m), 2.46-2.55 (2H, m), 2.62-2.73 (1H, m), 3.04-3.12 (1H, m),3.84-3.95 (3H, m), 4.03-4.14 (1H, m), 4.58 (1H, dd, J=10.4, 3.2 Hz),7.36 (2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz), 8.24 (1H, s), 8.28 (1H,d, J=2.4 Hz), 9.31 (1H, d, J=2.4 Hz), 9.68 (1H, brs).

Example 216:(S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one

To a mixture of1-(4-(2-chloro-4-isopropylpyrimidin-5-yl)phenyl)pyrrolidin-2-one (60 mg,0.19 mmol),(S)-2′-amino-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(88 mg, 0.38 mmol) in DMF (4 mL) was added con.HCl (50 uL). The reactionmixture was stirred at 80° C. for 36 hours to give a brown solution.LCMS showed the purity of product is 8% (Rt=0.905 min; MS Calcd: 510.2;MS Found: 511.4 [M+H]⁺). The mixture was purified by prep-HPLC (0.225%FA as an additive) purification to give(S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one(4.2 mg, yield: 4%) as a white solid.

1H NMR (400 MHz, DMSO-d₆) δ 0.78-0.84 (1H, m), 0.84-0.95 (1H, m),0.95-1.04 (1H, m), 1.04-1.12 (1H, m), 1.15 (3H, d, J=7.2 Hz), 1.17 (3H,d, J=7.2 Hz), 1.95-2.03 (1H, m), 2.05-2.14 (2H, m), 2.16-2.24 (1H, m),2.46-2.55 (2H, m), 3.02-3.14 (1H, m), 3.88 (2H, t, J=6.8 Hz), 4.00 (1H,t, J=10.4 Hz), 4.14-4.22 (1H, m), 4.61 (1H, dd, J=10.8, 2.8 Hz), 7.35(2H, d, J=8.4 Hz), 7.75 (2H, d, J=8.4 Hz), 8.22 (1H, s), 8.30 (1H, d,J=2.8 Hz), 9.17 (1H, d, J=2.4 Hz), 9.66 (1H, brs).

The following compounds were prepared according to the general proceduredescribed herein, as well as the individual procedure for anystructurally related compounds. The procedure utilized the appropriatereagents, solvents, and starting materials according to the finalproducts. All reactions were carried out under suitable conditions,including but not limited to temperature, pressure, and time.

Table 1 illustrates compounds of the invention that were prepared inaccordance with any of the synthetic method described above usingsuitable starting materials, reagents and appropriate and necessaryconditions to these compounds.

Example Compound Name Structure 217 N,N-dimethyl-4-(6-((1-(methylsulfonyl)- 2,3-dihydro-1H- pyrido[2,3-b][1,4]-oxazin-7-yl)amino)- pyridin-3-yl)bnz- amide

218 4-(6-((5-(2-(dimethyl- amino)-2-oxoethyl)- pyridin-3-yl)amino)-pyridin-3-yl)-N,N- dimethylbenzamide

219 N-methyl-4-(6-((5-(2- oxopyrrolidin-1-yl)- pyridin-3-yl)amino)-pyridin-3-yl)benz- amide

220 4-(6-acetamido- pyridin-3-yl)-N,N- dimethylbenzamide

221 N,N-dimethyl-4-(6- ((2-oxo-1,2-dihydro- pyridin-4-yl)amino)-pyridin-3-yl)benz- amide

222 4-(6-((5-(3-(4-amino- benzyl)-2-oxoimid- azolidin-1-yl)pyridin-3-yl)amino)pyridin- 3-yl)-N,N-dimethyl- benzamide

223 4-(6-((5-(3-(3-amino- benzyl)-2-oxoimid- azolidin-1-yl)pyridin-3-yl)amino)pyridin- 3-yl)-N,N-dimethyl- benzamide

224 4-(6-((5-(3-(3-(3-(3- aminophenyl)propan- amido)benzyl)-2-oxoimidazolidin-1-yl)- pyridin-3-yl)amino)- pyridin-3-yl)-N,N-dimethylbenzamide

225 (E)-4-(6-((5-(3-(3-(3- (3-(4-(dimethylamino)- but-2-enamido)phenyl)-propanamido)benzyl)- 2-oxoimidazolidin-1- yl)pyridin-3-yl)amino)-

pyridin-3-yl)-N,N- dimethylbenzamide 226 4-(6-((5-(3-(3-(2-aminoacetamido)- benzyl)-2-oxoimid- azolidin-1-yl)pyridin-3-yl)amino)pyridin- 3-yl)-N,N-dimethyl- benzamide

227 (E)-4-(6-((5-(3-(3-(2- (4-(dimethylamino)- but-2-enamido)-acetamido)benzyl)- 2-oxoimidazolidin- 1-yl)pyridin-3-yl)-

amino)pyridin-3-yl)- N,N-dimethylbenz- amide 228 4-(6-((5-(3-(4-(2-aminoacetamido)- benzyl)-2-oxoimid- azolidin-1-yl)pyridin-3-yl)amino)pyridin- 3-yl)-N,N-dimethyl- benzamide

229 (E)-4-(6-((5-(3-(4-(2- (4-(dimethylamino)- but-2-enamido)-acetamido)benzyl)- 2-oxoimidazolidin- 1-yl)pyridin-3-yl)-amino)pyridin-3-yl)- N,N-dimethylbenz- amide

230 4-(6-((5-(3-(4-(3-(3- aminophenyl)propan- amido)benzyl)-2-oxoimidazolidin- 1-yl)pyridin-3-yl)- amino)pyridin-3-yl)-

N,N-dimethylbenz- amide 231 (E)-4-(6-((5-(3-(4- (3-(3-(4-(dimethyl-amino)-but-2- enamido)phenyl)- propanamido)- benzyl)-2-oxoimid-azolidin-1-yl)pyridin- 3-yl)amino)pyridin- 3-yl)-N,N-dimethyl- benzamide

232 N-(5-((5-(4-(dimethyl- carbamoyl)phenyl)- pyridin-2-yl)amino)-pyridin-3-yl)-1H- benzo[d]imidazole- 7-carboxamide

233 1-(4-(6-((1-(1-hydroxy- cyclopropane-1- carbonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]- oxazin-7-yl)amino)- pyridin-3-yl)phenyl)-pyrrolidin-2-one

234 1-(4-(6-((1-(2-hydroxy- propanoyl)-2,3- dihydro-1H-pyrido-[2,3-b][1,4]oxazin-7- yl)amino)pyridin-3- yl)phenyl)pyrrolidin- 2-one

235 1-(4-(6-((1-(2-hydroxy- acetyl)-2,3-dihydro- 1H-pyrido[2,3-b][1,4]-oxazin-7-yl)amino)- pyridin-3-yl)phenyl)- pyrrolidin-2-one

236 (S)-2-((5-(4-((R)-4- hydroxy-2-oxo- pyrrolidin-1-yl)-phenyl)pyridin-2- yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2- d][1,4]oxazin-9-one

237 (S)-2-((5-(4-((S)-4- hydroxy-2-oxo- pyrrolidin-1-yl)-phenyl)pyridin-2-yl)- amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

238 1-(4-(6-((1-(2-hydroxy- 2-methylpropanoyl)- 2,3-dihydro-1H-pyrido[2,3-b][1,4]- oxazin-7-yl)amino)- pyridin-3-yl)phenyl)-pyrrolidin-2-one

239 5-methoxy-N-(5-((5- (4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)pyridin-3- yl)nicotinamide

240 6-oxo-N-(5-((5-(4-(2- oxopyrrolidin-1-yl)- phenyl)pyridin-2-yl)-amino)pyridin-3-yl)- 1,6-dihydropyridine- 3-carboxamide

241 1-(4-(6-((5-(4-(3- methoxypropanoyl)- piperazin-1-yl)-pyridin-3-yl)amino)- pyridin-3-yl)phenyl)- pyrrolidin-2-one

242 (S)-N,N-dimethyl-4- (6-((9-oxo-6a,7,8,9- tetrahydro-6H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-2-yl)- amino)pyridin-3-yl)- benzamide

243 2,3-difluoro-N-(5-((5- (4-(2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)pyridin-3- yl)benzamide

244 (R)-1-(4-(6-((5-(4- (tetrahydrofuran-3- carbonyl)piperazin-1-yl)pyridin-3-yl)- amino)pyridin-3- yl)phenyl)pyrrolidin- 2-one

245 (S)-1-(4-(6-((5-(4- (tetrahydrofuran-3- carbonyl)piperazin-1-yl)pyridin-3-yl)- amino)pyridin-3-yl)- phenyl)pyrrolidin- 2-one

246 (S)-2-((5-(3-fluoro-4- (2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

247 N-(5-((5-(4-(2-oxo- pyrrolidin-1-yl)- phenyl)pyridin-2-yl)-amino)pyridin-3-yl)- 2-phenylcyclopro- pane-1-carboxamide

248 1-ethyl-6-oxo-N- (5-((5-4-(2-oxo- pyrrolidin-1-yl)-phenyl)pyridin-2-yl)- amino)pyridin-3-yl)- 1,6-dihydropyridine-3-carboxamide

249 6-ethoxy-N-(5-((5-(4- (2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)pyridin-3- yl)nicotinamide

250 2-methyl-N-(5-((5-(4- (2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)pyridin-3- yl)morpholine-4- carboxamide

251 N-(5-((5-(4-(2-oxo- pyrrolidin-1-yl)- phenyl)pyridin-2-yl)-amino)pyridin-3-yl)- morpholine-4-carbox- amide

252 (1S,2S)-2-ethoxy- N-(5-((5-(4-(2-oxo- pyrrolidin-1-yl)-phenyl)pyridin-2- yl)amino)pyridin-3- yl)cyclopropane-1- carboxamide

253 5-methoxy-N-(5-((5- (4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)pyridin- 3-yl)-1H-benzo[d]- imidazole-7-carbox- amide

254 N-(5-((5-(4-(2-oxo- pyrrolidin-1-yl)- phenyl)pyridin-2-yl)amino)pyridin-3- yl)-2H-tetrazole-5- carboxamide

255 (S)-8,8-dimethyl-2- ((5-(4-(2-oxopyrrol- idin-1-yl)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

256 3-methyl-N-(5-((5- (4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)pyridin- 3-yl)piperazine-1- carboxamide

257 3-cyclopropyl-N-(5- ((5-(4-(2-oxopyrrol- idin-1-yl)phenyl)-pyridin-2-yl)amino)- pyridin-3-yl)piper- azine-1-carboxamide

258 (S)-2-((5-(3-fluoro- 4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)-8,8- dimethyl-6,6a,7,8- tetrahydro-9H- pyrido[2,3-b]pyrrolo-[1,2-d][1,4]oxazin-9- one

259 (6aS)-8-methyl-2-((5- (4-(2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

260 (S)-2′-((5-(4-(2-oxo- pyrrolidin-1-yl)- phenyl)pyridin-2-yl)amino)-6a′,7′- dihydro-6′H,9′H- spiro[cyclopropane-1,8′-pyrido[2,3-b]- pyrrolo[1,2-d][1,4]- oxazin]-9′-one

261 (6aS)-2-((5-(3-fluoro- 4-(2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)-8-methyl- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

262 2-cyclopropyl-N- (5-((5-(4-(2-oxo- pyrrolidin-1-yl)-phenyl)pyridin-2- yl)amino)pyridin-3- yl)morpholine-4- carboxamide

263 (S)-2-((4′-(difluoro- methyl)-5-(2-oxo- pyrrolidin-1-yl)-[2,3′-bipyridin]-6′-yl)- amino)-6,6a,7,8-tetra- hydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]- oxazin-9-one

264 N,N-dimethyl-4-(2- (pyridin-3-ylamino)- pyrimidin-5-yl)- benzamide

265 (R)-8-((5-(4-(2- oxopyrrolidin-1-yl)- phenyl)pyridin-2-yl)-amino)-3a,4-dihydro- 1H,3H-oxazolo- [3,4-d]pyrido[2,3-b][1,4]oxazin-1-one

266 (S)-2-((4-(2-amino- propan-2-yl)-5-(2- fluoro-4-(2-oxo-pyrrolidin-1-yl)- phenyl)pyridin-2- yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

267 (6aS)-2-((5-(3-fluoro- 4-(2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)-8-hydroxy- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

268 (6aS)-8-hydroxy-2- ((5-(4-(2-oxopyrrol- idin-1-yl)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

269 (6aR)-2-((5-(4-(1- methyl-2-oxopyrrol- idin-3-yl)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2d][1,4]- oxazin-9-one

270 (6aS,8R)-2-((5-(3- fluoro-4-(2-oxopyrrol- idin-1-yl)phenyl)-pyridin-2-yl)amino)- 8-hydroxy-8-methyl- 6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]- pyrrolo[1,2-d][1,4]- oxazin-9-one

271 (6aS,8R)-8-hydroxy- 8-methyl-2-((5-(4-(2- oxopyrrolidin-1-yl)-phenyl)pyridin-2-yl)- amino)-6,6a,7,8-tetra- hydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]- oxazin-9-one

272 1-(5-((5-(3-fluoro-4- (2-oxopyrrolidin-1- yl)phenyl)pyridin-2-yl)amino)pyridin-3- yl)imidazolidin-2-one

273 (S)-2-((4-(3-methoxy- cyclobutyl)-5-(4-(2- oxopyrrolidin-1-yl)-phenyl)pyrimidin-2- yl)amino)-6,6a7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

274 (S)-2-((1′-(4-methyl- 4H-1,2,4-triazol-3-yl)-1′,2′,3′,6′-tetrahydro- [3,4′-bipyridin]-6-yl)- amino)-6,6a,7,8-tetra-hydro-9H-pyrido[2,3- b]pyrrolo[1,2-d][1,4]- oxazin-9-one

275 (S)-2-((5-(4-(4-methyl- 4H-1,2,4-triazol-3-yl)-piperazin-1-yl)pyridin- 2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

276 (S)-2-((5-(4-(4- methylpyridazin-3- yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

277 (S)-2-((5-(4-(4- methylisoxazol-5- yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

278 (S)-2-((4-isopropyl-5- (4-(5-methyl-1H- 1,2,3-triazol-1-yl)-phenyl)pyrimidin-2- yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

279 (S)-2-((5-(3-methyl-2- oxo-1-oxa-3,8-diaza- spiro[4.5]decan-8-yl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

280 (S)-2-((4-morpholino- 5-(4-(2-oxopyrrolidin- 1-yl)phenyl)pyrimidin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

281 (S)-2-((4-(4-methyl- piperazin-1-yl)-5- (4-(2-oxopyrrolidin-1-yl)phenyl)pyrimidin- 2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

282 (S)-2-((4-(methoxy- methyl)-5-(4-(4- methylisoxazol-3-yl)phenyl)pyridin-2- yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

283 (S)-2-((5-(4-(4-methyl- isoxazol-3-yl)phenyl)- pyridin-2-yl)amino)-6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]- pyrrolo[1,2-d][1,4]- oxazin-9-one

284 (S)-2-((4-cyclobutoxy- 5-(4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

285 (S)-2-((4-cyclopropyl- 5-(4-(4-methyl-4H- 1,2,4-triazol-3-yl)-phenyl)pyridin-2-yl)- amino)-6,6a,7,8-tetra- hydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]- oxazin-9-one

286 (S)-2-((4-(3-methoxy- azetidin-1-yl)-5-(4- (2-oxopyrrolidin-1-yl)phenyl)pyrimidin- 2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

287 (S)-2-((4-methoxy-5- (4-(4-methyl-4H- 1,2,4-triazol-3-yl)-phenyl)pyrimidin-2- yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

288 (S)-2-((4-methoxy-5- (4-(5-methyl-1H- 1,2,3-triazol-1-yl)-phenyl)pyrimidin-2- yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido-[2,3-b]pyrrolo[1,2-d]- [1,4]oxazin-9-one

289 (S)-2-((5-(4-(5-methyl- 1H-1,2,3-triazol-1- yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

290 (S)-2-((4-methoxy-5- (4-(5-methyl-4H-1,2,4- triazol-3-yl)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro-9H- pyrido[2,3-b]pyrrolo-[1,2-d][1,4]oxazin-9- one

291 (S)-2-((5-(4-(4-methyl- 4H-1,2,4-triazol-3-yl)-phenyl)pyridin-2-yl)- amino)-6,6a,7,8-tetra- hydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]- oxazin-9-one

292 4-(4-(2-((2-(2,6- dioxopiperidin-3-yl)- 1,3-dioxoisoindolin-4-yl)oxy)acetamido)- butanamido)-N-(5- ((5-(4-(2-oxopyrrol-idin-1-yl)phenyl)- pyridin-2-yl)amino)- pyridin-3-yl)benz- amide

293 (S)-4-(4-(methoxy- methyl)-2-((9-oxo-6a, 7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo- [1,2-d][1,4]oxazin-2- yl)amino)pyrimidin-5-yl)-N,N-dimethyl- benzamide

294 (S)-4-(4-methoxy-2- ((9-oxo-6a,7,8,9-tetra- hydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]- oxazin-2-yl)amino)- pyrimidin-5-yl)-N,N-dimethylbenzamide

295 (R)-8-((5-(3-fluoro- 4-(2-oxopyrrolidin- 1-yl)phenyl)pyridin-2-yl)amino)-3a,4- dihydro-1H,3H- oxazolo[3,4-d]pyrido-[2,3-b][1,4]oxazin-1- one

296 4-(2-(2-(2-(2-((2- (2,6-dioxopiperidin- 3-yl)-1,3-dioxoiso-indolin-4-yl)amino)- ethoxy)ethoxy)- ethoxy)acetamido)- N-(5-((5-(4-(2-oxopyrrolidin-1-yl)- phenyl)pyridin-2-yl)- amino)pyridin-3-yl)-benzamide

297 (S)-2-((5-(4-(4-iso- butyl-4H-1,2,4-triazol- 3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d]-[1,4]oxazin-9-one

298 (S)-N,N-dimethyl-4- (2-((9′-oxo-6a′,7′- dihydro-6′H,9′H-spiro[cyclopropane- 1,8′-pyrido[2,3-b]- pyrrolo[1,2-d][1,4]-oxazin]-2′-yl)amino)- pyrimidin-5-yl)benz- amide

299 (S)-2-fluoro-N,N- dimethyl-4-(2-((9- oxo-6a,7,8,9-tetra-hydro-6H-pyrido[2,3- b]pyrrolo[1,2-d][1,4]- oxazin-2-yl)amino)-pyrimidin-5-yl)benz- amide

300 (S)-2-((5-(4-((R)-2- methyl-5-oxopyrrol- idin-1-yl)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

301 (S)-2-((5-(4-(pyrrol- idine-1-carbonyl)- phenyl)pyrimidin-2-yl)amino)-6,6a,7,8- tetrahydro-9H-pyrido- [2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one

302 (S)-2-((5-(4-(azetidine- 1-carbonyl)phenyl)- pyrimidin-2-yl)-amino)-6,6a,7,8-tetra- hydro-9H-pyrido[2,3- b]pyrrolo[1,2-d][1,4]-oxazin-9-one

303 (S)-N,N-dimethyl-4- (2-((9-oxo-6a,7,8,9- tetrahydro-6H-pyrido[2,3-b]pyrrolo- [1,2-d][1,4]oxazin-2- yl)amino)pyrimidin-5-yl)benzamide

304 (S)-2-((9-fluoro-5,5- dimethyl-8-(2- oxopyrrolidin-1-yl)-5H-chromeno[3,4- d]pyrimidin-3-yl)- amino)-6,6a,7,8-tetra-hydro-9H-pyrido[2,3- b]pyrrolo[1,2-d][1,4]- oxazin-9-one

305 (S)-2-((5-(4-(2-oxo- pyrrolidin-1-yl- 4,4,5,5-d4)phenyl)-pyridin-2-yl)amino)- 6,6a,7,8-tetrahydro- 9H-pyrido[2,3-b]-pyrrolo[1,2-d][1,4]- oxazin-9-one

Biochemical Assays Example 306: ADP-Glo Biochemical Assay

Dilution series of the compounds were prepared in DMSO at 100 times thefinal assay concentration (n₁=n₀/3 in 10 points). The compounds werefurther diluted to three times the assay concentration in assay buffer(20 mM MOPS pH 7.2, 25 mM magnesium chloride, 0.005% Tween 20). 6 μL ofthe diluted compounds were added to a 384 well assay plate followed by 9μL of a mix consisting of 4 nM PIP4K2A (full length protein, SignalChem)and 100 μM PI(5)P diC8 (Tebu-Bio). Enzyme and compounds werepre-incubated at room temperature for 15 minutes.

Then 3 μL of a solution containing 60 μM ATP (Promega) in assay bufferwas added to the wells containing compound and enzyme and mixing wasperformed by pipetting several times. The reaction was incubated at roomtemperature for 1 h. Then 18 μL of ADP-Glo™ Reagent (Promega) was addedto stop the kinase reaction and deplete the unconsumed ATP, mixing wasperformed by pipetting several times. The plate was incubated at roomtemperature for 40 minutes before addition of 36 μL of Kinase DetectionReagent (Promega) to convert ADP to ATP and introduce luciferase andluciferin to detect ATP. The reaction was incubated at room temperaturefor 40 minutes before the luminescence was measured in a in a Victor 3V1420 multilabel counter (Perkin Elmer).

Percent inhibition of the compounds as compared to dimethyl sulfoxidetreated control samples was calculated. Compound concentration versuspercent inhibition were fitted to generate IC₅₀ values. Results obtainedwith this assay are disclosed in Tables 2-4 below.

Example 307: Assay Protocol—PIP4KtypeIIA

GST tagged PIP4KtypeIIA and B enzymes were overexpressed in E. Coli andpurified to >80% homogeneity. Phosphatidyl inositol-5-phosphate (PI5P,Cat. #850152, Avanti Polar Lipids Inc.) was used as the lipid substrateand phosphatidyl ethanolamine (DOPE 18:1, Cat. #850725, Avanti PolarLipids Inc.) was used as the carrier lipid for assays. Ultrapure ATP andGTP was purchased from Bellbrooke Labs. ADP Glo reagents were obtainedfrom Promega. Transcreener FI reagent was obtained from Bellbrooke labs.

Buffers:

1. HEPES buffer mix: 200 mM HEPES pH 7.4, 50 mM MgCl₂, 0.05% v/vtriton×100.

2. HNE buffer: 20 mM HEPES, pH 7.4, 100 mM NaCl, 0.5 mM EGTA

3. H:E buffer: 30 mM HEPES, pH 7.4, 1 mM EGTA

Enzyme preparation: GST-tagged PIP4KtypeIIA (5 μL, 1.43 mg/mL) wasdiluted (1:10) to 50 μL using HNE buffer. From the 1:10 diluted stock, a6.4 μL aliquot was diluted further to 5 mL using HNE buffer to yield 5×enzyme stock (2.5 nM).

GST-tagged PIP4KtypeIIB (3.4 μL, 2.77 mg/mL) was diluted to 5 mL usingHNE buffer to yield 5× enzyme stock (25 nM)

Lipid Preparation: In a 10 mL pyrex glass vial, 1 μg of PI5P and 1 μg ofDOPE were suspended in 2.5 mL of HEPES buffer mix and 2.5 mL of H:Ebuffer. The contents were mixed and sonicated for 3 min to yield atranslucent lipid stock.

Compound Preparation: Compounds were stored as 5 mM stocks in neat DMSOas room temperature in glass vials. 5 mM stocks were diluted to 2 mM andthen serially diluted (3×) in neat DMSO in 96 well polypropylene plates.From the serially diluted stocks, 3 μL was delivered into 250 μL of 25%DMSO (in water) to generate 5× compound stocks. Typically, the highestcompound conc. was 24 μM.

Example 308: PIP4KtypeIIA Inhibition Assay

The assay volume was kept at 25 μL. To each well of the reaction plate,10 μL of lipid stock (1:1 ratio PI5P:DOPE) was delivered. This wasfollowed by the addition of 5 μL of compound in 25% DMSO. Then, to eachwell, 5 μL of 2.5 nM (5λ) typeIIA enzyme was delivered. The contentswere mixed well and incubated for 1 h at 27° C. After 1 h, reaction wasinitiated by adding 5 μL of 50 μM ATP and the contents were mixed wellwith a multi-channel pipetteman. The final concentration of the reagentsare as follows: 50 mM HEPES, pH 7.3, 10 mM MgCl₂, 20 mM NaCl, 0.01% v/vtriton-X100, 5% DMSO, 10 μM ATP, 80 μM (2 μg) PI5P, 2 μg DOPE, and 0.5nM PIP4KIIA. Typically, the highest conc. of compounds was 4.8 μM andthe lowest conc. was 0.

After 1 h, the reaction was quenched by adding 25 μL of ADP Glo reagent.The contents were incubated for 1 h. Afterwards, 50 μL of kinasedetection reagent was delivered. The contents were incubated for anotherhour. The luminescence was read using Molecular Devices Paradigm platereader. Each plate had a “No inhibitor” control (max. activity, 4 wells)and a blank (background noise, 4 wells). The blanks were averaged andsubtracted from all other wells. Using a calibration curve, RLU wasconverted to μM ADP (product). IC50 was calculated by plotting theresidual activity (expressed as % No inhibitor control) vs. log [Inh.conc.]

Example 309: PIP4KtypeIIB Inhibition Assay

The assay volume was kept at 25 μL. To each well of the reaction plate,10 μL of lipid stock (1:1 ratio PI5P:DOPE) was delivered. This wasfollowed by the addition of 5 μL of compound in 25% DMSO. Then, to eachwell, 5 μL of 25 nM (5×) typeIIB enzyme was delivered. The contents weremixed well and incubated for 1 h at 27° C. After 1 h, reaction wasinitiated by adding 5 μL of 500 μM GTP and the contents were mixed wellwith a multi-channel pipetteman. The final concentration of the reagentsare as follows: 50 mM HEPES, pH 7.3, 10 mM MgCl₂, 20 mM NaCl, 0.01% v/vtriton-X100, 5% DMSO, 100 μM GTP, 80 μM (2 μg) PI5P, 2 μg DOPE, and 5 nMPIP4KIIB Typically, the highest conc. of compounds was 4.8 μM and thelowest conc. was 0.

After 2 h, the reaction was quenched by adding 25 μL of transcreener FIreagent. The contents were incubated at rt for 1 h and the Fluorescence(Ex: 584 Em: 623) was read using Molecular Devices Paradigm platereader. Each plate had a “No inhibitor” control (max. activity, 4 wells)and a blank (background noise, 4 wells). The blanks were averaged andsubtracted from all other wells. Using a calibration curve, RFU wasconverted to μM GDP (product). IC₅₀ was calculated by plotting theresidual activity (expressed as % No inhibitor control) vs. log [Inh.conc.]

Table 2 represents PI5P4K activity of compounds (Example No.) of theinvention arranged in accordance with the inhibition of PIP4K2 A kinaseassay.

Kinase Assay- PIP4K2 A IC₅₀ ≤ 1 nM 81 222 223 226 227 183 177 179 278280 284 288 215 Kinase Assay- PIP4K2 A 1 < IC₅₀ ≤ 10 nM 73 76 23 78 4374 94 100 102 103 97 90 93 85 86 96 224 225 117 119 109 111 230 231 138141 143 232 131 155 233 132 152 156 163 164 151 234 235 150 238 239 242246 252 258 190 84 178 191 174 267 268 89 92 276 277 281 282 283 286 287289 290 294 202 197 Kinase Assay- PIP4K2 A 10 < IC₅₀ ≤ 100 nM 38 24 4042 217 11 28 77 52 75 26 25 31 12 72 13 59 46 45 53 80 79 99 101 98 9587 58 50 91 113 114 116 118 139 140 121 122 123 128 130 135 136 137 142126 120 129 124 157 133 127 134 154 159 165 166 162 240 241 153 192 285291 293 297 Kinase Assay- PIP4K2 A 100 < IC₅₀ ≤ 1000 nM 1 82 19 56 57 1469 47 218 34 16 27 41 39 68 65 32 30 67 63 20 21 18 17 104 106 49 48 88115 61 62 107 125 112 108 110 147 146 148 149 158 161 236 237 264 274275 292 175 296 Kinase Assay- PIP4K2 A IC₅₀ > 1000 nM 10 66 33 3 54 35 937 6 36 219 7 2 64 70 5 220 4 8 221 22 60 71 51 228 229 29 160 279Table 3 represents PI5P4K activity of compounds (Example No.) of theinvention arranged in accordance with the inhibition of ADP-glo kinaseassay PIP4K 2A.

ADP-glo kinase assay PIP4K 2A IC₅₀ ≤ 1 nM 210 211 212 200 195 216ADP-glo kinase assay PIP4K 2A 1 < IC₅₀ ≤ 10 nM 73 81 222 223 224 226 227109 111 230 231 138 155 233 163 164 151 234 150 238 242 246 247 249 255258 260 261 183 84 265 266 203 206 198 204 201 199 207 205 182 178 181177 172 179 176 197 295 ADP-glo kinase assay PIP4K 2A 10 < IC₅₀ ≤ 100 nM80 94 100 102 103 95 85 86 89 96 225 113 116 117 118 119 139 140 121 135136 137 141 142 143 232 124 131 157 133 146 127 132 134 152 156 154 235165 166 162 239 252 253 254 256 169 170 168 259 173 167 190 208 196 192187 191 174 267 268 270 271 ADP-glo kinase assay PIP4K 2A 100 < IC₅₀ ≤1000 nM 59 46 45 101 98 106 87 58 50 49 114 61 62 107 122 123 125 128130 126 120 129 112 108 110 147 158 161 159 236 237 240 241 153 244 245272 250 251 257 262 ADP-glo kinase assay PIP4K 2A IC₅₀ > 1000 nM 60 10471 51 228 229 148 149 29 160 243 194 269Table 4: represents PI5P4K activity of compounds (Example No.) of theinvention arranged in accordance with the inhibition of PIP4K2 B kinaseassay.

Trans-FI P kinase assays: PIP4K2B 1 < IC₅₀ ≤ 10 nM 260 210 211 203 212198 204 201 200 199 196 195 207 205 178 177 179 276 278 280 284 286 287288 289 290 294 215 202 216 197 Trans-FI P kinase assays: PIP4K2B 10 <IC₅₀ ≤ 100 nM 73 81 94 100 99 103 95 97 90 93 85 86 89 92 91 96 222 223224 225 226 113 227 116 117 119 230 231 121 130 135 136 137 138 141 142143 232 131 155 133 233 134 152 156 163 164 151 154 234 235 150 238 162239 153 242 246 247 249 253 255 258 169 170 168 259 173 261 167 183 19084 265 266 208 206 192 182 187 181 191 172 267 268 176 270 271 277 281282 283 285 291 292 293 295 297 59 46 45 80 101 102 98 106 87 58 50 114118 109 111 139 140 107 122 123 125 128 126 120 129 124 157 146 127 132158 161 159 165 236 166 240 241 244 245 272 250 251 252 254 256 257 262174 274 275 175 296 Trans-FI P kinase assays: PIP4K2B IC₅₀ > 1000 nM 60104 71 51 49 88 115 61 62 228 229 112 108 110 147 148 149 29 160 237 243194 269 279

Equivalents

Those skilled in the art will recognize, or be able to ascertain, usingno more than routine experimentation, numerous equivalents to thespecific embodiments described specifically herein. Such equivalents areintended to be encompassed in the scope of the following claims.

The invention claimed is:
 1. A compound of Formula (Ie):

or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,stereoisomer, or tautomer thereof, wherein:

represents a double bond; A is C₃₋₈ cycloalkyl, C₄₋₈ cycloalkenyl, aryl,spiroheterocyclyl, heterocyclyl, or 6-membered heteroaryl; a, b, c, andd, are each independently C, CH, or N, wherein at least one of a, b, c,and d is N; and no more than two of a, b, c, and d are N; X₄ and Z₁ areeach independently —O—, —N(R₁₅)—, or —C(R₁₅)(R₁₅)—; ω is 1, 2, or 3; Wis C(R₆) or N; R₁ is —N(R₂)C(O)R₃, —C(O)N(R₂)(R₃), —S(O)₂N(R₂)(R₃),—N(R₂)S(O)₂R₃, —R₂C(O)N(R₂)(R_(c3)), or heteroaryl, wherein heteroarylis optionally substituted with one or more R₇; R₂ is independently, ateach occurrence, C₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein theC₁₋₆ alkyl, C₂₋₆ alkenyl, or C₂₋₆ alkynyl is optionally substituted withone or more R₄; R₃ is independently, at each occurrence, —H, C₁₋₆ alkyl,C₂₋₆ alkenyl, or C₂₋₆ alkynyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, orC₂₋₆ alkynyl is optionally substituted with one or more R₄; or R₂ and R₃when taken together with the atom to which they are each attached form aheterocycle optionally substituted with one or more R₄; R₄ isindependently, at each occurrence, —H, halogen, —OH, —NH₂, —NO₂, —CN,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl is optionally substituted with one ormore R₇; R₅ is —H, halogen, —OH, —CN, C₁₋₆ alkyl, methoxy, —O—C₃-C₆alkyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl; R₆ is —H,halogen, —OH, —NH₂, —NO₂, —CN, —CO₂H, —C(O)NH₂, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, —O—C₃₋₈ cycloalkyl, or C₁₋₆ alkyl, wherein theC₁₋₆ alkyl, C₁₋₆ alkoxy, heterocyclyl, or C₃₋₈ cycloalkyl is optionallysubstituted with —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, —NH₂,—NH(C₁₋₆ alkyl), or —N(C₁₋₆ alkyl)₂; or R₅ and R₆ when taken togetherwith the carbon atom to which they are each attached form a 5- to6-membered heteroaryl ring; R₇ is independently, at each occurrence, —H,halogen, —OH, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the C₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈cycloalkyl, heterocyclyl, aryl, or heteroaryl is optionally substitutedwith one or more R₁₄; R₁₄ is independently, at each occurrence, —H,halogen, —CN, —NO₂, —OH, —NH₂, C₁₋₆ alkyl, C₃₋₈ cycloalkyl,heterocyclyl, aryl, or heteroaryl; R₁₅ is independently, at eachoccurrence, —H, halogen, oxo, —OH, —NH₂, —NO₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, —C(O)N(R₂₁)(R₂₃),—(CH₂)_(o)—C(O)R₂₃, —OC(O)R₂₃, —C(O)OR₂₃, —SO₂R₂₃,—N(R₂₃)C(O)—Ar—N(R₂₃)-G, or —N(R₂₃)C(O)—Ar—N(R₂₃)C(O)-G, wherein theC₁₋₆ alkyl, C₁₋₆ alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, oraryl is optionally substituted with one or more R₂₃; or two R₁₅ groups,together with the atoms to which they are attached, form a heterocyclyl,C₃₋₆ cycloalkyl, C₅₋₆ spirocycloalkyl, aryl, or heteroaryl, wherein theC₃₋₆ cycloalkyl, heterocyclyl, C₅₋₆ spirocycloalkyl, heteroaryl, or arylis optionally substituted with one or more R₂₀; Ar is aryl; G is —H,C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl,heterocyclyl, aryl, heteroaryl, —C(O)OR₂₃, —C(O)CH═CHCH₂N(R₂₃)(R₂₃), or—C(O)N(R₂₁)(R₂₃); or two R₁₅ when on adjacent atoms may be takentogether with the atoms to which they are each attached to form aheterocycle optionally substituted with one or more R₁₆; R₁₆ isindependently, at each occurrence, C₁₋₆ alkyl, C₃₋₆ cycloalkyl,—C(O)R₂₃, —C(O)R₂₃, —C(O)OR₂₃, —S(O)₂R₂₃, or oxo; R₂₀ is independently,at each occurrence, —H, halogen, —OH, —NH₂, oxo, —C(O)R₂₁, —OR₂₃, C₃₋₆cycloalkyl, or C₁₋₆ alkyl; R₂₁ is independently, at each occurrence, —H,C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl,aryl, or heteroaryl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionallysubstituted with one or more —H, halogen, —CN, —OH, C₁₋₆ alkyl, C₁₋₆alkoxy, C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl; each R₂₃ isindependently, at each occurrence, —H, C₁₋₆ alkyl, C₁₋₆ alkoxy, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, orheteroaryl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substitutedwith one or more —H, halogen, —CN, —OH, —NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, aryl, or R₂₄; R₂₄ isindependently, at each occurrence, —H, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₈ cycloalkyl, heterocyclyl, aryl, heteroaryl, C(O)N(C₁₋₆alkyl)(C₁₋₆ alkyl), —C(O)—C₁₋₆ alkyl, —C(O)—C₂₋₆ alkenyl, or —C(O)O—C₁₋₆alkyl, wherein the C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈cycloalkyl, heterocyclyl, heteroaryl, or aryl is optionally substitutedwith one or more —H, halogen, —CN, —OH, —NH₂, C₁₋₆ alkyl, C₁₋₆ alkoxy,C₃₋₈ cycloalkyl, heterocyclyl, heteroaryl, or aryl; and each o isindependently 0-4.
 2. The compound of claim 1 selected from the groupconsisting of:(R)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-((R)-4-hydroxy-2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-((S)-4-hydroxy-2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyrazin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)—N,N-dimethyl-4-(6-((9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)benzamide,(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-8,8-dimethyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8,8-dimethyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aS)-8-methyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2′-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(6aS)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-methyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methoxypyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-methylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(3,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(2,5-difluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((6-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(R)-8-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-3a,4-dihydro-1H,3H-oxazolo[3,4-d]pyrido[2,3-b][1,4]oxazin-1-one,(S)-2′-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2-((4-(2-aminopropan-2-yl)-5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2′-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2′-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2′-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2′-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2′-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6a′,7′-dihydro-6′H,9′H-spiro[cyclopropane-1,8′-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin]-9′-one,(S)-2-((3-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(2-methyl-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-cyclopropyl-5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-cyclopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)-4-isopropylpyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-isopropyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(2-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aS)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-hydroxy-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aS)-8-hydroxy-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-methoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-methyl-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aR)-2-((5-(4-(1-methyl-2-oxopyrrolidin-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aS,8R)-2-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-8-hydroxy-8-methyl-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(6aS,8R)-8-hydroxy-8-methyl-2-((5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-(methoxymethyl)-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(3S,6R)—N,N-dimethyl-6-(6-(((S)-9-oxo-6a,7,8,9-tetrahydro-6H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-2-yl)amino)pyridin-3-yl)tetrahydro-2H-pyran-3-carboxamide,(S)-2-((1′-(4-methyl-4H-1,2,4-triazol-3-yl)-1′,2′,3′,6′-tetrahydro-[3,4′-bipyridin]-6-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)piperazin-1-yl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(4-methylpyridazin-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(4-methylisoxazol-5-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-(methoxymethyl)-5-(4-(4-methylisoxazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(4-methylisoxazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-cyclobutoxy-5-(4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-cyclopropyl-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(5-methyl-TH-1,2,3-triazol-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((4-methoxy-5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-(4-methyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(R)-8-((5-(3-fluoro-4-(2-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-3a,4-dihydro-1H,3H-oxazolo[3,4-d]pyrido[2,3-b][1,4]oxazin-1-one,(S)-2-((5-(4-(4-isobutyl-4H-1,2,4-triazol-3-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,(S)-2-((5-(4-((R)-2-methyl-5-oxopyrrolidin-1-yl)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one,and(S)-2-((5-(4-(2-oxopyrrolidin-1-yl-4,4,5,5-d4)phenyl)pyridin-2-yl)amino)-6,6a,7,8-tetrahydro-9H-pyrido[2,3-b]pyrrolo[1,2-d][1,4]oxazin-9-one;or a pharmaceutically acceptable salt, prodrug, solvate, hydrate,stereoisomer, or tautomer thereof.
 3. A pharmaceutical compositioncomprising a compound of claim 1, and a pharmaceutically acceptablecarrier.
 4. A method of inhibiting PI5P4K comprising, administering to apatient in need thereof an effective amount of a compound of claim
 1. 5.The compound of claim 1, wherein A is phenyl.
 6. The compound of claim1, wherein R₁ is heteroaryl, wherein the heteroaryl is optionallysubstituted with R₇.
 7. The compound of claim 6, wherein R₇ is C₁₋₆alkyl.
 8. The compound of claim 1, wherein R₅ is —H, halogen, —OH, CN,or C₁₋₆ alkyl.
 9. The compound of claim 1, wherein W is C(R₆).
 10. Thecompound of claim 1, wherein R₆ is H.
 11. The compound of claim 1,wherein R₁₅ is H.